Ageing Research Reviews 100 (2024) 102409

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Ageing Research Reviews

journal homepage: www.elsevier.com/locate/arr

Review article

Heat stroke: Pathogenesis, diagnosis, and current treatment

Zhe Zhang a,1, Xiaopeng Wu a,1, Zheng Zou b,1, Mingzhi Shen c , Qiong Liu a , Ziyin Zhangsun a,
Huadong Zhao d, Wangrui Lei a , Zheng Wang e, Yushu Dong b,* , Yang Yang a,*
a
Xi’an Key Laboratory of Innovative Drug Research for Heart Failure, Northwest University First Hospital, Faculty of Life Sciences and Medicine, Northwest University,
229 Taibai North Road, Xi’an, 710069, China
b
Department of Neurosurgery, The General Hospital of Northern Theater Command, No. 83, Wenhua Road, Shenhe District, Shenyang, Liaoning 110016, China
c
Department of General Medicine, Hainan Hospital of Chinese PLA General Hospital, 80 Jianglin Road, Hainan, 572013, China
d
Department of General Surgery, Tangdu Hospital, The Airforce Medical University, 1 Xinsi Road, Xi’an, 710038, China
e
Department of Cardiothoracic Surgery, Central Theater Command General Hospital of Chinese People’s Liberation Army, 627 Wuluo Road, Wuhan, 430070, China

A R T I C L E I N F O A B S T R A C T

Keywords: Recently, the incidence of heat-related illnesses has exhibited a steadily upward trend, which is closely associated
Heat stroke with several environmental factors such as climate change and air pollution. The progression of heat-related
Heat-related illnesses illnesses is a continuous process and can progress to the terminal period when it transforms into heat stroke,
Disseminated intravascular coagulation
the most severe form. Heat stroke is markedly by a core body temperature above 40◦ C and central nervous
Multiple organ dysfunction syndrome
system dysfunction. Current knowledge suggests that the pathogenesis of heat stroke is complex and varied,
including inflammatory response, oxidative stress, cell death, and coagulation dysfunction. This review
consolidated recent research progress on the pathophysiology and pathogenesis of heat stroke, with a focus on
the related molecular mechanisms. In addition, we reviewed common strategies and sorted out the drugs in
various preclinical stages for heat stroke, aiming to offer a comprehensive research roadmap for more in-depth
researches into the mechanisms of heat stroke and the reduction in the mortality of heat stroke in the future.

1. Introduction conditions (heat edema, heat syncope, heat cramps, and heat exhaus-
tion), and heat stroke (the most severe form of heat-related illness)
Recently, the incidence of heat-related illnesses has been reported to (Schmidt, 2022; Sorensen and Hess, 2022). The occurrence of heat
be increasing yearly due to a variety of factors, such as climate change, stroke is intricately related to high temperature and humidity environ-
insufficient heat tolerance, air pollution, high humidity, and lack of air- ments, thermoregulation dysfunction, and excessive heat accumulation.
conditioning (Han et al., 2022; Puvvula et al., 2022). Heat-related ill- Initially, heat stress, due to hot and humid environments and/or stren-
nesses refer to a spectrum of syndromes that arise when an individual is uous exercise (Faurie et al., 2022), activates a thermoregulatory
exposed to elevated temperatures and/or high humidity, particularly response to increase cardiac output and redistribute blood supply, and
during intense physical exertion. Heat exposure can exacerbate the risk meanwhile dissipate heat through sweating (Grossmann et al., 2022).
of mortality for diverse diseases, including hypertension, diabetes, and Gradually, dehydration occurs due to massive loss of body fluids and
cardiovascular disease (CVD) (Burkart et al., 2021). A study published in prolonged sweating and inadequate rehydration. Severe dehydration
The Lancet-Planet Health shows an upward trend in additional mortality impairs blood circulation, leading to a heat-related condition: heat
caused by rising global temperatures, from 0.83 % in 2000–2003 to edema, heat syncope, heat cramps, and heat exhaustion (Glazer, 2005;
1.04 % in 2016–2019 (Zhao et al., 2021). This trend translates to an Sandor, 1997; Wexler, 2002). However, to maintain the essential oxygen
estimated 500,000 additional deaths worldwide each year due to supply to the brain and heart, the body has to shut down the blood
heat-related illnesses. Consequently, there is a pressing need to enhance circulation in the skin, stopping sweating and causing adiaphoresis. As a
our understanding of these illnesses. result, the hypothalamic thermoregulatory center loses control of body
Heat-related illnesses span a continuum, encompassing mild temperature and the core temperature rises rapidly beyond the

* Correspondence to: Xi’an Key Laboratory of Innovative Drug Research for Heart Failure, Northwest University First Hospital, Faulty of Life Sciences and
Medicine, Northwest University, 229 Taibai North Road, Xi’an 710069, China.
E-mail addresses: [email protected] (Y. Dong), [email protected] (Y. Yang).
1
These authors contributed equally to this work.

https://doi.org/10.1016/j.arr.2024.102409
Received 5 February 2024; Received in revised form 2 July 2024; Accepted 4 July 2024
Available online 8 July 2024
1568-1637/© 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.
Z. Zhang et al. Ageing Research Reviews 100 (2024) 102409

Table 1
Comparison of different heat-related illness.
Heat-related illness Type Mechanisms Symptoms Treatments References

Heat edema Mild The capillaries on the body surface Edema (usually in the hands and feet) with Supportive managements, including (Sandor, 1997;
dilate and the blood flow rate increases, dizziness, loss of appetite, and general keeping away from hot environments, Wexler, 2002)
causing an increase in capillary weakness. cool water flushing.
filtration pressure and edema.
Heat syncope Mild Loss of electrolytes in the body Exhaustion, restlessness, dizziness, Keep away from hot environment, (Sandor, 1997;
(especially sodium depletion), and headache or nausea, vomiting, pale face, ventilate, replenish electrolytes (light Wexler, 2002)
inadequate one-off cerebral blood flow.
cold skin, rapid and shallow breathing, saline), and adequate rest. If syncope
rapid and weak pulse. In severe cases, occurs, change the patient’s position to
muscle twitching in the lower limbs and side-lying with the head lowered.
abdomen, difficulty breathing, or even
fainting.
Heat cramps Moderate Loss of electrolytes in the body Spasms of the limbs and abdominal wall Similar to heat syncope. (Sandor, 1997;
(especially sodium depletion). muscles occur, accompanied by sweating, Wexler, 2002)
fine breathing, vomiting, dizziness,
increased body temperature, thirst, and
tachycardia.
Heat exhaustion Moderate Similar to heat cramps. Increased body temperature, excessive Cooling, rest, hydration, intravenous (Glazer, 2005;
sweating, fatigue, malaise, vertigo, fluids (in case of severe reduction of blood Sandor, 1997;
headache, decreased judgment, nausea volume and electrolyte disorders), and Wexler, 2002)
and vomiting, and sometimes muscle monitoring of blood biochemical tests
spasms, postural vertigo and syncope, (sodium and potassium levels; phosphate,
without obvious signs of neurological calcium and magnesium metabolism in
damage. serum).
Heat stroke Severe Being in a hot, humid, windless Hyperpyrexia, anhidrosis, and mental Rapid cooling (rapid reduction of core (Glazer, 2005;
environment and/or engaging in high- status changes, MODS (liver and kidney body temperature to below 39◦ C within Sandor, 1997)
intensity training or heavy physical dysfunction, gastrointestinal impairment, 10–40 min, below 38.5◦ C in 2 h), fluid
labor leads to disruption of the cardiovascular insufficiency), coagulation resuscitation (injection of crystalloid such
thermoregulatory center and dysfunction, rhabdomyolysis and other as saline or glucose; diuretics such as
subsequent increased heat production, complications (hyperkalemia, furosemide if urine volume is not up to
excessive heat absorption, and impaired hyperphosphatemia, hypocalcemia, and standard; supplementation of sodium
heat expenditure. myoglobinuria). bicarbonate to alkalize urine to pH >
5.5), hemodialysis (hemofiltration
therapy), sedation and analgesia, tracheal
intubation, correction of coagulation
disorders, anti-infection, enteral
nutrition, anti-inflammatory and
immunomodulation.

temperature set point. More alarmingly, as the core temperature (rectal measures (such as heat protection gear, timely hydration and rest, and
temperature) reaches up to 40◦ C/104 ◦ F (this temperature is currently heat dissipation) can minimize the incidence of heat stroke.
controversial and questioned, with some studies also writing In this review, we summarized the current research progress on the
40.5◦ C/105 ◦ F) (Armstrong et al., 2007; Casa et al., 2015), the combined pathophysiology and pathogenesis of heat stroke from the following
impact of hyperthermia and circulatory failure leads to multiorgan aspects: inflammatory response, oxidative stress, cell death, coagulation
dysfunction (Cottle et al., 2022). Such a critical illness syndrome is dysfunction, genomic predisposition, and Gastrointestinal microbial
known as heat stroke. Table 1 compared the different heat-related ill- translocation. We also introduced common strategies and sorted out
nesses from various aspects. (Glazer, 2005; Sandor, 1997; Wexler, multiple drugs in various preclinical stages for heat stroke treatment,
2002). which may help to furnish a theoretical basis for a more in-depth study
Heat stroke is a perilous medical condition, manifesting as burning on the mechanisms of heat-related illnesses, especially heat stroke.
skin, adiapneustia, convulsions, vomiting, impaired consciousness (e.g.,
delirium, convulsions, coma), and multi-organ dysfunction. The key 2. General aspects of heat stroke
distinction between typical heat stroke and severe cases lies in the pa-
tient’s loss or impending loss of consciousness (Bouchama and Knochel, 2.1. The classifications of heat stroke
2002; Liu et al., 2020b). Patients usually enjoy a more favorable prog-
nosis if their core body temperature (CBT) is successfully reduced to Heat stroke includes two distinct types: exertional heat stroke (EHS)
below 40℃ within 30 minutes after onset. If cooling measures are and classic heat stroke (CHS, also known as non-exertional heat stroke).
delayed, it can lead to dementia, speech or movement disorders, and an These two forms differ significantly in terms of their susceptible pop-
increased death rate. Heat stroke’s pathogenesis encompasses not only ulations, predisposing factors, and mortality rates.
thermoregulatory disorders, but also inflammatory responses, oxidative EHS is characterized by neuropsychiatric impairment and a high core
stress, cellular scorching, autophagy, and apoptosis, involving multiple body temperature (typically >40.5◦ C/105 ◦ F), and commonly occurs in
molecules and signals, such as NLRP3 (Zhang et al., 2021), healthy young adults who perform strenuous activities in hot weather,
TLR4/MyD88 (Rosenberger et al., 2015), HMGB1 (Geng et al., 2015), such as military personnel, athletes and porters. EHS results from
Nrf2/HO-1 (He et al., 2019), ZBP1 (Yuan et al., 2022), and p53 (Gu reduced heat dissipation from the body after several hours of intense
et al., 2014). Currently, hypothermia control, rehydration therapy and physical activity. In severe cases, it can lead to complications like
hemodialysis are the primary treatment modalities for heat stroke. rhabdomyolysis, acute renal injury, liver dysfunction, disseminated
While there has been significant research into symptomatic therapeutics intravascular coagulation, or multiple organ dysfunction syndrome,
for heat stroke, most of these are still in various preclinical stages. resulting in a high mortality rate (Knapik and Epstein, 2019; Roberts
Fortunately, heat stroke is highly preventable. Avoiding strenuous et al., 2021).
physical work in a hot environment and taking adequate protective On the other hand, CHS is caused by high temperature and/or high

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Z. Zhang et al. Ageing Research Reviews 100 (2024) 102409

Fig. 1. Specific manifestations of heat stroke in various organs. High temperature environment leads to heat stress of the body, triggering a series of thermoreg-
ulatory responses (e.g., increased cardiac output, redistribution of blood supply, sweating to dissipate heat). When the situation progresses to the point where the
thermoregulatory center loses control of body temperature, the core temperature rises rapidly above 40◦ C. Subsequently, dysfunction occurs in several organs, such
as the brain, liver, kidney, and heart.

humidity environment, usually without strenuous physical activity. It is exertional febrile disease) (Davis et al., 2017; Lin et al., 2022), kidney
primarily attributed to excessive endogenous heat production. CHS is failure, gastrointestinal damage, and acute respiratory distress syn-
most commonly seen in people living in hot and poorly ventilated drome (ARDS) may also be observed. Moreover, the permeability
environment, especially in the elderly, pregnant women, and patients reducution of the gastrointestinal wall leads to leakage of endotoxins
with hypertension, diabetes, heart disease, and mental illness. In severe and pathogens into systemic circulation and overwhelming the detoxi-
cases, it can result in shock, cardiac arrhythmia and heart failure, pul- fication ability of the liver, eventually culminating in endotoxemia
monary edema, cerebral edema, and disseminated intravascular coag- (Graber et al., 1971; Lambert, 2004; Ogden et al., 2020a).
ulation (DIC). Most of the biochemical indexes of heat stroke are consistent with
the changes of various parameters in the hematologic-enzymatic phase
mentioned above. In addition to changes of enzymes and blood cells, the
2.2. Clinical symptoms, predisposing factors and biochemical indexes levels of various electrolytes in the blood also be affected, resulting in
blood biochemical characteristics of hyperkalemia, hyponatremia,
Clinically, heat stroke is identified as a syndrome of extremely high hypochlorhydria, hypocalcemia, and hyperphosphatemia (Bathini et al.,
fever, bleeding and coagulation disorders, circulatory failure, systemic 2020; Lim and Mackinnon, 2006).
inflammatory reaction, and multiple organ dysfunction (Fig. 1). The
diagnostic hallmarks of heat stroke encompass central nervous system 3. Physiopathology and pathogenesis of heat stroke
(CNS) dysfunction (impaired consciousness, seizures, or unconscious-
ness), coupled with hyperpyrexia (CBT exceeding 40◦ C), and a recent The underlying pathogenic mechanisms of heat stroke lie in the
history of exposure to intense heat (classical form) or strenuous physical disruption of the balance between heat production and heat dissipation,
exertion (exertional form) (Albukrek et al., 1997; Chao et al., 2020; Zhu resulting in excessive heat storage. In addition, critical pathophysio-
et al., 2023). In addition, heat stroke is characterized by an absence of logical progresses such as inflammatory response, oxidative stress, cell
sweating (which occurs more frequently in CHS) and is accompanied by death, and coagulation disorders are also involved in the occurrence and
increased heart rate, muscle cramps or weakness, and multiple organ development of heat stroke (Bouchama and Knochel, 2002).
injury. Coagulopathy, severe liver damage (an intrinsic feature of

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3.1. Inflammatory response altered in exosomes from patients with pyrexia, most of which were
enriched in signaling pathways related to inflammation (Li et al.,
The inflammatory response is a pivotal factor in the development of 2021c). In addition, miRNAs have been shown to be regulators of heat
heat stroke-induced MODS. Hyperthermia initiates a disruption of the stress-induced neuroinflammation. Li et al. found that heat stress
immune system, further leading to an unregulated systemic inflamma- significantly induces the release of various pro-inflammatory factors in
tory response and systemic coagulation, hemorrhage, and necrosis. microglia, such as IL-1β, IL-6 and TNF-α, and elevated the expression of
Diverse inflammation-related regulators, such as NOD-like receptor miR-155. They further found that miR-155 promotes the activation of
thermal protein domain associated protein 3 (NLRP3), toll-like receptor NF-κB signaling pathway, subsequently induces the release of the above
4 (TLR4), high-mobility group box 1 (HMGB1), Janus kinase 2 (JAK2) / pro-inflammatory cytokines by targeting inhibition of liver X receptor α
signal transducer and activator of transcription 3 (STAT3), and micro- (LXRα), promoting heat stress-induced neurological dysfunction (Li
RNAs (miRNAs) are involved in the systemic inflammatory response et al., 2019b). The above results indicate that miRNAs have great po-
syndrome (SIRS) associated with heat stroke. tential to regulate heat stroke induced-neurological damage. Further-
Upon stimulation, NLRP3 and pro-cysteinyl aspartate-specific more, it will be meaningful to develop a novel carrier of miRNAs,
proteinase-1 (pro-caspase-1) bind to apoptosis-associated speck-like exosome, capable of transporting drugs or therapeutic agents precisely
protein containing a CARD (ASC), forming NLRP3 inflammasome to the targeted damaged sites, thereby exerting therapeutic effects
complex. Subsequently, the activated NLRP3 inflammasome prompts through neurospecific target molecule guidance.
ASC to cleave pro-caspase-1 into active caspase-1, which in turn pro-
motes IL-1β and IL-18 maturation and ultimately induces inflammation. 3.2. Oxidative stress
Yan and coworkers found that heat exposure can activate NLRP3
inflammasome and IL-1β through the above processes, thereby inducing Oxidative stress arises from an imbalance between oxidation and
liver injury (Geng et al., 2015). In contrast, Zhang et al. recently antioxidant, characterized by the abnormally production of reactive
demonstrated that heat treatment alone fails to activate NLRP3 oxygen species (ROS) and reactive nitrogen species (RNS). The excessive
inflammasome in the hypothalamus, and no significant systemic production of ROS is an important contributor to HS-induced apoptosis
inflammation or neuroinflammation is observed (Zhang et al., 2021). and inflammation. ROS scavenger N-acetyl-L-cysteine (NAC) pretreat-
The varying degrees of injury observed in diverse organs during the ment significantly inhibits HS-induced receptor interacting protein ki-
progression of heat stroke could potentially explain the disparity in nases 1 (RIPK1)/RIPK3-dependent necroptosis both in vivo and in vitro
NLRP3 inflammasome activity following heat treatment. Notably, in the and intestinal injury (Li et al., 2020). Moreover, Gu and colleagues
hypothalamus of mice with previously inflammatory infection [mice found that intense HS significantly increases ROS in human umbilical
that were pretreated with lipopolysaccharide (LPS) to mimic a poten- vein endothelial cells (HUVECs), triggering oxidative stress damage and
tially inflammatory state], activation of NLRP3 inflammasome is pro- activating mitochondrial-induced apoptosis (Gu et al., 2014). Mecha-
moted after heat stress (Zhang et al., 2021). The above results suggest nistically, the ROS overproduction promotes the translocation of p53
that the NLRP3/IL-1β-induced inflammatory response may be an from the cytoplasm to mitochondria, and leads to elevated mitochon-
important factor in the pathology of heat stroke, especially with prior drial membrane potential (MMP/ΔΨm), increased cytochrome c release,
infection. activated caspase-9 and caspase-3, and ultimately apoptosis (Gu et al.,
The interaction of TLR4 and ligands [e.g., LPS, heat shock protein 2014). In addition, ROS acts as a potent enhancer of HS-induced
(HSP), HMGB1] at the cell membrane, thereby initiating downstream inflammation, stimulating the NF-κB inflammatory pathway and upre-
signaling and leading to inflammation (Dehbi et al., 2012). Rosenberger gulating the expression of pro-inflammatory cytokines like IL-1, IL-6,
and colleagues indicated that HSP60 (the major protein in response to and IL-8 (Tsai et al., 2021). On the other hand, ROS elevates NLRP3
heat stress during hyperthermia) injected intrathecally could have direct levels, and promotes the production of NLRP3 inflammasome (Zhang
toxic effects on the central nervous system (CNS) through TLR4/MyD88 et al., 2019).
signaling induced inflammation, including neuronal death, axonal Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important
damage, oligodendrocyte loss, and demyelination (Rosenberger et al., transcription factor regulating intracellular redox homeostasis. Heme
2015). Hence, TLR4-mediated inflammatory response may be a poten- oxygenase 1 (HO-1, the downstream regulator of Nrf2) is a key antiox-
tial mechanism of neurological impairment and subsequent symptoms in idant enzyme, which can catalyze the catabolism of heme to resist the
heat stroke. damage of oxygen free radicals. Many researches have demonstrated
HMGB1 is a key mediator of inflammation in heat stroke and is that Nrf2/HO-1 signaling axis plays a key role in HS-induced multiple
closely associated with various organ damage and endotoxemia (Wang organs oxidative damage, including lung, liver, brain and intestine. Zeng
et al., 1999). Inhibition of HMGB1 prevents NLRP3/IL-1β-induced he- et al. observed that elevated HO-1 in type II alveolar cells reverses
patocyte pyroptosis and liver inflammation to ameliorate liver injury in congested and thickened lung septa induced by HS, alleviating heat
heat stroke rats (Geng et al., 2015). Binding of HMGB1 and receptor for stroke-induced pulmonary lesions (Tseng et al., 2021). As a protein with
advanced glycation end products (RAGE) activates downstream high antioxidant activity, camel whey protein (CWP) enhances the
signaling, such as mitogen-activated protein kinase (MAPK) and nuclear expression of Nrf2 and HO-1 in the liver of HS rats, then inhibits ROS
factor kappa B (NF-κB), thereby inducing the renal inflammation in heat production and nicotinamide adenine dinucleotide phosphate oxidase
stroke mice (Xue et al., 2021). Furthermore, Dehbi et al. reported that (NOX) activity, reduces malondialdehyde (MDA) and glutathione (GSH)
HMGB1 interacts with TLR4, which then upregulates IL-1β and IL-6 to level, increases superoxide dismutase 1 (SOD1) activity, eventually
initiate an inflammatory response (Dehbi et al., 2012). These results increasing total antioxidant capacity (TAC) of the liver (Du et al., 2022).
suggest that HMGB1 may serve as a potential therapeutic target for Additionally, pretreatment with antioxidant, such as ferulic acid (FA)
MODS in heat stroke. and punicalagin (PUN), in rat small intestinal epithelial cells (ICE-6),
In addition, several miRNAs are also implicated in promoting in- increases phosphorylation of Nrf2 and its nuclear translocation through
flammatory response during heat stroke. miRNAs are a class of non- activating the PI3K/Akt signaling pathway, subsequently upregulates
coding single-stranded RNA molecules of approximately 22 nucleo- HO-1 expression, thus preventing intestinal epithelial barrier dysfunc-
tides in length encoded by endogenous genes, and are involved in post- tion induced by HS (He et al., 2019; Xu et al., 2016). In summary,
transcriptional regulation of gene expression through destabilizing or Nrf2/HO-1 signaling axis, a key signal regulating oxidative stress, has
inhibiting translation of target mRNAs (Lagos-Quintana et al., 2001; Lau now exhibited therapeutic potential of multi-organ dysfunction in heat
et al., 2001; Lee and Ambros, 2001). A clinical analysis study showed stroke, making it a potentially advantageous target for future clinical
that, compared to healthy volunteers, 202 miRNAs were significantly treatment strategies.

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3.3. Cell death Pyroptosis is associated with inflammation, in which NLRP3

inflammasome plays a crucial role. Zhang et al. observed that ROS,
In addition to cellular necrosis directly caused by thermal injury, NOX4, NLRP3, caspase-1 and IL-1β expression are significantly elevated
many other mechanisms or manifestations of cell death exist in heat in the liver of heat stroke rats (Zhang et al., 2019), hinting that pyrop-
stroke. Common programmed cell death includes ferroptosis, apoptosis, tosis is associated with ROS-NLRP3 signaling. Moreover, Yan and team
necroptosis, autophagy, and pyroptosis. These forms of cell death are found that the activation of NLRP3 inflammasome in the HS rats’ liver is
mediated by various signaling pathways/molecules, such as acyl-CoA mediated by HMGB1, which subsequently activates IL-1β to induce he-
synthetase long-chain family member 4 (ACSL4)-mediated ferroptosis, patocytes pyroptosis (Geng et al., 2015). However, there are still fewer
p53-mediated apoptosis, RIPK3-mediated necroptosis, dynamin-related studies on HS-induced pyroptosis, and the underlying mechanism still
protein 1 (Drp1)-mediated autophagy, and NLRP3 inflammasome- needs to be deeply explored.
mediated pyroptosis.
Ferroptosis (the main cause of skeletal muscle cell death in RM and 3.4. Coagulation disorders
AKI complicated by EHS) is driven by ACSL4 and GPX4-mediated iron-
dependent lipid peroxidation (Sha et al., 2021). He et al. found that Heat stroke can cause severe coagulation disorders and even develop
yes-associated protein (YAP) mediates the upregulation of ACSL4 and into DIC. The mechanism of coagulation dysfunction may lie in hyper-
reduction of glutathione peroxidase 4 (GPX4) through TEA structural fibrinolysis. A study of 18 patients with severe heat stroke showed that,
domain transcription factor 1 (TEAD1)/TEAD4 (He et al., 2022). These the whole-blood tissue factor, thrombin-antithrombin complex (TAT),
processes result in elevated lipid peroxidation levels and tissue accu- and soluble thrombomodulin (TM) levels dramatically increased, while
mulation of non-heme iron in skeletal muscle tissue of EHS. Conversely, the levels of the major physiologic anticoagulants were significantly
inhibition of ACSL4 reverses the above processes, leading to significant decreased, including platelet, antithrombin, protein C, and protein S
improvement of ferroptosis in skeletal muscle cells and enhancement of (Huisse et al., 2008; Mustafa et al., 1985). Besides, extensive hemor-
tissue damage (He et al., 2022). rhage and thrombosis, leukocyte transmigration and microvascular
The apoptosis induced by intense HS is closely related to the mito- endothelial damage were observed in baboon with heat stroke, accom-
chondrial function. Roberts et al. observed widespread apoptosis in the panied by increased staining of endothelial von Willebrand factor
spleen, intestine and lung, as well as in hematopoietic cells, of baboon (vWF), tissue factor (TF), and endothelial leukocyte-platelet interaction
heat stroke model (Roberts et al., 2008). In-depth studies revealed that (Roberts et al., 2008). Additionally, a recent study by Proctor et al. in-
oxidative stress (ROS generation) in heat stroke stimulates the trans- dicates that the number of platelets in the blood is reduced in heat stroke
location of p53 to mitochondria. This translocation is manifested by mice, but the morphological changes suggest that platelets continue to
elevated mitochondrial membrane potential (ΔΨm), the release of cy- be produced and even tend to become more active (Proctor et al., 2020).
tochrome c, and the activation of caspase-3 and caspase-9, ultimately Meanwhile, levels of D-dimer and soluble thrombomodulin elevate
leading to widespread apoptosis (Gu et al., 2014; Li et al., 2019a). during the early and middle stages of heat stroke, while D-dimer levels
Yuan and team found that HS directly induces RIPK3-dependent decrease during the most severe period of organ damage, hinting po-
necroptosis. Mechanistically, HS induces heat shock protein 1 (HSP1) tential fibrinolysis-resistant thrombosis (Proctor et al., 2020). The above
binding to the promoter of the Z-DNA binding protein 1 (ZBP1, an results suggest that the coagulation dysfunction caused by heat stroke
intracellular pattern recognition receptor) gene, and enhancing ZBP1 has a potential stage variability, and coagulation markers may be used as
expression through the receptor interaction protein isoform interaction indicators for monitoring the severity of heat stroke and the therapeutic
motif (RHIM) domain (Yuan et al., 2022). Notably, though previous process.
studies have shown that ZBP1 activation is usually dependent on the
binding of the Zα-domain to Z-nucleic acid (Jiao et al., 2020), research 3.5. Gastrointestinal microbial translocation
by Yuan reveals a novel activation mechanism of ZBP1 that is inde-
pendent of the nucleic acid-sensing, providing a new idea for the pre- In heat stroke patients, the disrupted equilibrium between heat
vention and treatment of heat stroke. production and heat dissipation results in excessive heat storage and
HS induces autophagy through distinct signaling pathways. Yi and blood redistribution through increasing blood flow to the skin to aid in
colleagues found that HS impairs lysosomal function and triggers heat dissipation. This process significantly diminishes intestinal blood
autophagy through protein kinase RNA–like endoplasmic reticulum ki- flow and enhances intestinal epithelial tight junction permeability
nase (PERK)-eukaryotic translation initiation factor 2α (eIF2α) pathway, (Dokladny et al., 2006). Consequently, toxic microorganisms in the gut
alleviating heat-induced inflammation (Dong et al., 2017). P62, a reg- translocate and infiltrate the circulation through the gastric mucosa,
ulatory protein of autophagy degradation located on the mitochondrial triggering a series of deleterious reactions, including inflammatory
membrane, exhibits a negative correlation with the extent of autophagy response, DIC, and MODS. Disruption of the intestinal epithelial tight
degradation. Hu et al. found that p62 expression is reduced in heat junction can be attributed to the direct death of intestinal epithelial cells
stroke rats, resulting in dysfunctional autophagy degradation (Hu et al., (Chow and Zhang, 1998), enhanced oxidative stress and elevated in-
2021). Similarly, AMPK/Unc-51-like kinase 1(ULK1, a key protein for flammatory factors in the gut (Oliver et al., 2012), and disruption of the
autophagy initiation)-induced autophagy is blocked in the liver of heat sustained expression of HSPs and heat shock factor (HSF) (Dokladny
stroke rat (Hu et al., 2021). Besides, Drp1 is an important mitochondrial et al., 2006). The specific mechanisms of the first two have been
division regulatory protein. Zhang et al. found that Sheng Mai San, a described in the subsection "Oxidative stress" above, while HSPs and
Chinese medicine formulae, promotes mitochondrial fission and HSF maintain the gastrointestinal barrier function mainly through the
mitophagy through activation of AMPK and phosphorylation at the regulation of occludin, cadherin, myosin, and connexin. HSF1 mediates
Ser616 of Drp1, thus relieving HS-induced liver injury (Zhang et al., the up-regulation of occludin expression by binding to the promoter
2022). Notably, HMGB1 is a dual regulator of autophagy and mitoph- sequence nGAAnnTTCn (Dokladny et al., 2008). Varasteh et al. observed
agy. On the one hand, cytoplasmic HMGB1, a beclin 1 (autophagy key that l-Arginine protects the gastrointestinal barrier integrity by pro-
regulatory protein) binding protein, positively regulates autophagy moting NO synthesis and E-cadherin expression (Varasteh et al., 2018).
through interaction with the ligand RAGE. On the other hand, HMGB1 HSP70 is involved in the above process and one of the mechanisms may
improves the mitochondrial fission and energy metabolism homeostasis lie in the inhibition of myosin light chain kinase (MLCK) phosphoryla-
through upregulating HSP27 (Kang et al., 2011). In summary, auto- tion (Yang et al., 2007). In addition, Apg-2 (a member of the HSP110
phagy with multi-signal and multi-target may serve as a potential family) interacts with the SH3 structural domain of the tight junction
approach for precise treatment of HS. adaptor protein ZO-1, activating the transcriptional activity of

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Table 2
A review of preclinical potential drugs for the treatment of heat stroke.
Drugs Type Pharmacological effects References

IL-1 receptor antagonist Biological IL-1 receptor antagonist restores homeostatic function and limits multi-organ damage (Lin et al., 1995)
medicine during heat stroke.
HMGB1 monoclonal antibody Biological HMGB1 monoclonal antibody improves liver function and reduces inflammation in heat (Tong et al., 2013)
medicine stroke rats.
Huanglian Chinese Huanglian ameliorates HS-mediated brain injury and neuroinflammation in mice by (Moon et al., 2017)
medicine attenuating the upregulation of HSPs and c-Fos.
Ginkgo biloba extracts Chinese Nano delivery of Ginkgo biloba extracts, EGb-761 and BN-52021, shows superior (Chen et al., 2006)
medicine neuroprotective effects in heat stroke.
Recombinant human thrombomodulin Biological Recombinant human thrombomodulin reduces heat stroke-induced disseminated (Ohbe et al., 2019)
medicine intravascular coagulation.
Dexmedetomidine Chemical Dexmedetomidine attenuates heat stroke-induced neuroinflammation by activating (Li et al., 2021b)
medicine PI3K/Akt and targeting TREM2 in microglia.
Mesenchymal stem cell (MSC) Biological MSCs injection restores astrocyte function and inhibits microglia overactivation induced (Wang et al., 2021;
medicine by heat stroke. Zhang et al., 2020)
Xanthine oxidase inhibitors (allopurinol) Chemical Allopurinol reduces LPS-induced inflammation in portal vein and protects the integrity (Hall et al., 2001)
medicine of tight intercellular connections.
Sodium tanshinone IIA Chemical Sodium tanshinone IIA improves DIC in rats through dilating microarteries, inhibiting (Chen et al., 2017)
medicine platelet coagulation, and promoting fibrinolysis in CHS.
Bacillus licheniformis Biological The intestinal probiotic Bacillus licheniformis maintains intestinal barrier integrity in (Li et al., 2021a)
medicine HS rats by alleviating intestinal damage and improving tight connections.
Eicosapentaenoic acid Chemical Eicosapentaenoic acid reduces intestinal permeability and plasma endotoxin levels, (Xiao et al., 2015)
medicine effectively alleviates intestinal structural damage caused by HS.
PARP inhibitor Chemical PARP inhibitor can increase the expression of HSPs, reducing heat stroke-induced liver (Mota et al., 2008)
medicine injury.
17-dimethylaminoethylamino-17- Chemical 17-DMAG upregulates Hsp70 and phosphorylates AMPK, attenuating hypotension and (Tsai et al., 2016)
demethoxy-geldanamycin (17-DMAG) medicine organ dysfunction induced by HS.
Melatonin Chemical Melatonin alleviates the hyperthermia and hypotension caused by HS, reduces the (Lin et al., 2018, 2011;
medicine expression of systemic pro-inflammatory factors, weakens neutrophil infiltration, and Wu et al., 2012)
finally prolongates the survival time of HS rats with MODS.
Salidroside Chinese Salidroside prevents heat stroke-caused myocardial damage of mice by antioxidative (Chen et al., 2019)
medicine and anti-inflammatory activity.
Quercetin Chinese Quercetin ameliorates heat stroke-induced myocardial damage by antioxidative and (Lin et al., 2017)
medicine anti-inflammatory activity.
Geranylgeranylacetone Chemical Geranylgeranylacetone, a non-toxic inducer of HSP70, improves heat-induced hepatic (Zhao et al., 2010)
medicine and renal dysfunction and inflammation of rats.
ROS scavengers (mannitol, α-tocopherol, N- Chemical ROS scavengers inhibit HS-induced RIPK1/RIPK3-dependent necroptosis formation to (Li et al., 2020)
acetyl-L-cysteine) medicine prevent HS-induced intestinal damage via scavenging ROS production.
Magnolol and flavonoid baicalin Chinese Magnolol and flavonoid baicalin are both effective in preventing and repairing cerebral (Chang et al., 2007)
medicine ischemia and oxidative damage during heat stroke.

ZO-1-associated nucleic acid binding protein (ZONAB) and regulating stroke is total cold water immersion, which can rapidly reduce core body
intracellular signaling and cell proliferation of epithelial cells under heat temperature. Examples include rapid rotation of ice water-soaked towels
shock conditions (Tsapara et al., 2006). on the head, trunk and extremities, and rapid rotation of ice packs on the
neck, armpits and groin (Armstrong et al., 1996). A systematic evalua-
4. Therapeutic strategies tion from Douma and team analyzed the effects of water immersion
techniques after heat stroke in 63 studies. They showed that the use of
Clinical treatments for heat stroke are divided into general therapy water at 1–17◦ C is more effective in reducing core body temperature
(e.g., promoting heat dissipation, electrolyte replacement), physical (Douma et al., 2020). Further, hypothermic retrograde jugular vein flush
therapy (e.g., cooling), and pharmacotherapy which has been clinically (HRJVF) improves brain oxidative stress, systemic inflammation and
used or pre-clinical studied (Table 2). In addition, a large number of ischemic injury in HS rats by reversing level changes of multiple
preclinical studies have proposed many novel therapeutic approaches HS-induced damage markers, such as d-dimer, protein C, TNF-α, creat-
for the different heat stroke pathogenesis, including inflammatory inine (Hsu et al., 2006).
response, oxidative stress, coagulation disorders, and multi-organ dis- In addition to TTM, fluid resuscitation, blood purification, and
orders, but have yet to be validated in clinical trials (Table 3). clinical drugs are also commonly used in clinical emergencies for heat
stroke (Liu et al., 2020a). For early mild heat injury, oral administration
of Huoxiang Zhengqi Liquid, external use of wind oil or cooling oil and
4.1. General treatment other traditional Chinese medicine can prevent heat stroke in advance.
For severe patients with heat stroke, patients are prone to multiple
Targeted temperature management (TTM) is particularly important complications, and symptomatic drug treatment can be carried out or
for patients with heat stroke (Stanger et al., 2018), aiming to maintain used for clinical first aid. For example, Angong Niuhuang Wan, a clas-
rectal temperature at 37.0◦ C to 38.5◦ C (Liu et al., 2020b). The first step sical prescription, is often used to treat stroke and cerebral hemorrhage
in the treatment of patients with heat stroke is internal and external caused by severe heat stroke in clinic. Actually, physical therapy is
cooling: enhanced ventilation externally, cold/ice water gavage or drug usually used for cooling treatment in clinical, and there is no specific
treatment to cool down internally. For example, bedside blood filtration drug for prevention or treatment, but related symptoms and emergency
and cold liquid intravenous drip are all commonly used to rapidly reduce treatment can be achieved by using Chinese patent medicines as well as
the patient’s temperature in clinic (Bouchama et al., 2007). It is also Western medicine including epinephrine and dexamethasone injection.
necessary to strengthen monitoring and protect the function of multiple In addition to the clinical drugs already used, several preclinical drugs,
organs. such as PARP inhibitor, IL-1 receptor antagonist have only been studied
Available evidence suggests that the gold standard treatment for heat

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Z. Zhang et al. Ageing Research Reviews 100 (2024) 102409

Table 3 Furthermore, they migrate into lung, kidney, and spleen at 24 h after
General and potential treatments targeting each pathogenesis of heat stroke. HS, effectively mitigating acute systemic inflammation and vascular
Pathogenesis Treatments References endothelial injury (Umemura et al., 2018). Similarly, human umbilical
cord blood-derived CD34+ cells therapy improves multi-organ
Disorders of Cooling (including bedside blood (Liu et al., 2020b;
thermoregulatory filtration and cold liquid Stanger et al., 2018) dysfunction by attenuating systemic inflammation (Chen et al., 2007).
center and intravenous drip), fluid Cytokines are intimately involved in the development of inflamma-
electrolyte resuscitation, blood purification, tion. IL-1 receptor antagonist restores homeostatic function and limits
and tranquilizer (e.g., propofol, multi-organ damage during heat stroke (Lin et al., 1995). Early endog-
benzodiazepines).
Inflammatory response Anti-inflammatory drugs (such (Garcia et al., 2020;
enous expression of IL-6 may prevent the development of inflammation
as dexamethasone and Lin et al., 1995; Liu and preposition protection against intestinal damage in heat stroke mice
ibuprofen), cytokine antagonists, et al., 2014, 2020a; (Phillips et al., 2015). In addition, pretreatment with HMGB1 mono-
and cell transplantation. Umemura et al., clonal antibody downregulates levels of AST and ALT (hepatic injury
2018)
biomarkers), and suppresses expression of several pro-inflammatory
Oxidative stress ROS scavengers (e.g., (Chang et al., 2007a,
α-tocopherol, and Alad-1 or its 2007b; Tsai et al., factors in heat stroke rats (Tong et al., 2013). Hence, the application
analogs), Sheng Mai San, 2021) of counterpart antagonist or specific antibody may alleviate the in-
Magnolol, and flavonoid flammatory response in heat stroke.
baicalin.
Coagulation disorders Coagulation factors (Hagiwara et al.,
supplementation, platelet 2010; Kawasaki
4.3. Targeting oxidative stress
supplementation, anticoagulants et al., 2014; Ohbe
(heparin), and thrombomodulin. et al., 2019) Undoubtedly, hyperthermia, cerebral ischemia, and hypotension
Infection Antibiotics (cephalosporin II (Liu et al., 2020a) result from heat stroke intertwine with oxidative stress (Chang et al.,
antibiotics), and antifungals.
2007a). Therefore, antioxidant therapy is also a direction for the future
Multi-organ Nerve damage: Huang Lian and (Chen et al., 2019,
dysfunction Ginkgo biloba extracts, 2006; Hall et al., treatment of heat stroke. Li et al. determined that the scavenging of ROS
dexmedetomidine, MSCs 2001; Hii et al., prevents heat stroke-induced intestinal damage. Furthermore, Alad-1,
injection; 2022; Li et al., 2021; an agonist of aldehyde dehydrogenase 2 (ALDH2), reduces heat
Intestinal damage: xanthine Lin et al., 2017; Lin stroke-induced ROS accumulation and attenuates oxidative stress (Tsai
oxidase inhibitors, misoprostol, et al., 2018; Lin
eicosapentaenoic acid; et al., 2011; Moon
et al., 2021). Remarkably, regular and daily exercise for at least three
Heart, liver and kidney damage: et al., 2017; Mota weeks significantly attenuates heat shock-induced overproduction of
geranylgeranylacetone, et al., 2008; Tsai hydroxyl radicals and lipid peroxidation (Chang et al., 2007b). In
salidroside, quercetin, PARP et al., 2016; Wang addition, the traditional Chinese herbal medicines including Magnolol,
inhibitor, 17-DMAG. et al., 2021; Wu
and flavonoid baicalin have been found to be effective in preventing and
et al., 2012; Xiao
et al., 2015; Zhang repairing cerebral ischemia and oxidative damage during heat stroke
et al., 2020; Zhao (Chang et al., 2007b).
et al., 2010)
4.4. Targeting coagulation disorders
in preclinical studies (Table 2).
Multiple studies have demonstrated that recombinant thrombomo-
dulin plays an important role in the treatment of DIC resulting from heat
4.2. Targeting inflammatory response stroke. An observational clinical study conducted in Japan showed that
treatment with recombinant human thrombomodulin significantly
Therapies targeting the heat stroke-induced inflammatory response lowers patient mortality (Ohbe et al., 2019). In addition, earlier in-
include anti-inflammatory drugs, cellular therapy, and cytokine antag- vestigations have established that heparin can counteract DIC after heat
onists/agonists. However, these potential treatments are in various stroke (Hagiwara et al., 2010; Kawasaki et al., 2014). Sodium tan-
stages of research and data are still limited. shinone IIA improves DIC in rats through dilating microarteries, inhib-
Glucocorticoids [dexamethasone (DXM), hydrocortisone, and iting platelet coagulation and promoting fibrinolysis (Chen et al., 2017).
methylprednisolone] and epinephrine, are commonly used drugs for the
treatment of heat stroke-induced inflammation in the clinic (Liu et al., 4.5. Targeting multiple organ dysfunction
2020a). Glucocorticoid are frequently administered in critical situa-
tions, such as persistent high fever ≥39◦ C, along with multiple or large Nerve damage is a hallmark of heat stroke. Chinese medicine Huang
solid lesions and/or shadows on lung that progress rapidly over a short Lian and Ginkgo biloba extracts exert protective effects on neurological
period of time; significant respiratory distress, and meeting the diag- injury. Huanglian ameliorates heat stroke-mediated brain injury and
nostic criteria for severe ARDS (Liu et al., 2020a). DXM, an immuno- neuroinflammation in mice by attenuating the upregulation of HSPs and
suppressive drug, controls inflammation and alleviates HS-induced c-Fos (Moon et al., 2017). Nano delivery of Ginkgo biloba extracts, such
organ damage via reducing the expression of pro-inflammatory cyto- as EGb-761 and BN-52021, showed superior neuroprotective effects
kines and attenuating the hypercoagulable state in HS rats (Liu et al., (Chen et al., 2006). In addition, dexmedetomidine exerts neuro-
2014). Furthermore, the combination of DXM with other drugs has been protective effects by activating PI3K/Akt and targeting TREM2 in
shown to be therapeutically beneficial in treating neurological damage microglia to attenuate neuroinflammation in heat stroke (Li et al.,
caused by heat stroke. Propofol reduces cellular damagethrough inhib- 2021b). Furthermore, mesenchymal stem cell (MSC) injection restores
iting intracellular HMGB1 release (Tang et al., 2013). In addition, Garcia astrocyte function and inhibits microglia overactivation in heat stroke
et al. demonstrated that ibuprofen alleviates EHS-induced intestinal (Wang et al., 2021; Zhang et al., 2020).
damage by its anti-inflammatory properties (Garcia et al., 2020; Tang Intestinal damage in heat stroke typically results from a breakdown
et al., 2013). in the integrity of the intestinal barrier. Xanthine oxidase inhibitors
Umemura and colleagues reported a bone marrow-derived mono- (allopurinol) reduce portal vein lipopolysaccharide levels and improve
nuclear cell (BMMNC) transplantation therapy. Intravenous injection of intestinal function by protecting the integrity of tight intercellular
BMMNCs secretes anti-inflammatory factors and reduces pro- connections (Hall et al., 2001). Misoprostol treatment mitigates ROS and
inflammatory cytokines at 3, 6, and 12 h after heat stroke. apoptosis of goblet cells and cytotoxicity caused by heat stroke, and

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Z. Zhang et al. Ageing Research Reviews 100 (2024) 102409

prevents intestinal barrier destruction in heat stroke rats (Hii et al., hyperthermia and hypotension caused by heat stroke, reduces the
2022). The intestinal probiotic Bacillus licheniformis maintains intesti- expression of systemic pro-inflammatory factors, weakens neutrophil
nal barrier integrity in heat stroke rats by alleviating intestinal damage infiltration, and finally prolongates the survival time of heat stroke rats
and improving tight connections (Li et al., 2021a). Eicosapentaenoic with MODS, which can be used as a novel drug for the early treatment in
acid significantly reduces intestinal permeability and plasma endotoxin heat stroke (Lin et al., 2018, 2011; Wu et al., 2012).
levels, effectively alleviating intestinal structural damage caused by HS,
thus enhancing the integrity of the supporting epithelial barrier (Xiao 5. Discussion and perspectives
et al., 2015). Moreover, l-Arginine restores NO synthesis and attenuates
E-calmodulin downregulation induced by HS, to protect intestinal Heat stroke is a life-threatening medical condition resulting from
epithelial integrity (Varasteh et al., 2018). Simply, aerobic exercise is central thermoregulation disorder through a variety of complex patho-
effective in preventing heat stress-induced impairment of gastrointes- genesis, such as inflammation, oxidative stress, coagulation disorders,
tinal integrity as well as microbial translocation (Ogden et al., 2020b). and cell death. As the environmental temperature continues to rise
Antioxidants such as N-acetylcysteine (NAC) and glutathione (GSH) annually, the morbidity and mortality of heat stroke are also escalating.
synthesized substrates have potent gastrointestinal barrier protective Heat stroke leads to extensive injury, accompanied by a variety of
effects (Oliver et al., 2012). serious complications, such as dementia, MODS, and DIC. Although a
A variety of medicines have been demonstrated to improve the heart, large number of clinical and basic researches have focused on heat
liver, and kidney damage in heat stroke. For example, salidroside and stroke in recent years, the specific mechanism of heat stroke has not
quercetin both prevent myocardial damage of mice caused by heat been clarified, thus limiting targeted clinical treatment options. There-
stroke (Chen et al., 2019; Lin et al., 2017). In addition, PARP inhibitor, fore, the development of new adjuvant therapy, which can effectively
poly (ADP-ribose) polymerase-1 inhibitor, and 17-dimethylaminoethy- control inflammatory response and offset multiple organ complications,
lamino-17-demethoxy-geldanamycin (17-DMAG) all increase the are urgent problems to be solved in the treatment of heat stroke. Besides,
expression of HSPs and reduce heat stroke-induced liver injury (Mota clinical studies on heat stroke are mostly limited to a small number of
et al., 2008; Tsai et al., 2016). Geranylgeranylacetone, a non-toxic cases, necessitating large-scale clinical cohort studies to gain a more
inducer of HSP70, improves heat-induced hepatic and renal dysfunc- comprehensive understanding of the disease and its treatment strategies.
tion in rats (Zhao et al., 2010). Importantly, therapies in the ICU will be Fortunately, heat stroke has the great preventability. The crucial pre-
taken to restore hemodynamics and prevent the development of MODS ventive strategies against heat stroke entail avoiding high temperature,
where liver failure is the most serious concern(Lin et al., 2022; Martí- high humidity and unventilated environment, and paying attention to
nez-Insfran et al., 2019). Furthermore, melatonin alleviates the heat stroke prevention, and immediately cooling down when early

Fig. 2. Risk factors for heat stroke. An overview of risk factors for heat stroke, including individual factors, medicine use, and environmental factors.

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Z. Zhang et al. Ageing Research Reviews 100 (2024) 102409

symptoms (coma and convulsion) appear. Identifying genetic signa- acclimatization training is essential for people at risk of heat stroke (such
tures, searching for new biomarkers and developing new adjuvant as athletes and labourers). Furthermore, after several generations of
therapies can be termed as the main directions for future research in the adaptation, the population living in a thermal environment for a long time
treatment of heat stroke. In addition, as heat stroke-related deaths are will establish a stable coordination relationship with the thermal climate
primarily attributed to central dysfunction due to hyperthermia and and have heritable characteristics (heat adaptation) (Liu et al., 2020a).
organ failure, exploring specific biomarkers targeting a specific Thus, identifying genetic traits that may reduce or increase a person’s
damaged organ may provide a more efficient diagnosis and prognostic ability to response to heat stress help clinicians more carefully judge the
index for the future clinical treatment of heat stroke-induced organ development of the disease.
damage.
Despite a significant rise in the incidence of heat stroke, there are Funding
only two aspects that contribute to the development of heat stroke:
heightened heat production and impaired heat dissipation. However, it This work was supported by the National Natural Science Foundation
is also noted that multiple intrinsic (e.g. age, biological sex, and other of China (82300319, 82070422, and 82200330), Key Medical Research
diseases, or injuries) and exterior factors (e.g. high temperature, high Projects in Xi’an City (24YXYJ0010), Natural Science Foundation of
humidity) can impact the risk and outcomes of patients with heat stroke Hubei Province (2023AFB965), Supported project by Hubei Provincial
(summarized in Fig. 2). For instance, the elderly are more susceptible to Administration of Traditional Chinese Medicine (ZY2023Q016),
heat stress than the young due to the weakened body temperature Research Plan Project of Shaanxi Institute of Basic Science (22JHQ053),
regulation mechanism (D’Souza et al., 2020). The biological sex may be Qinchuangyuan Traditional Chinese Medicine Innovation Research and
the distinct factors in response to heat stress. Recent researches reported Development Transformation Project (2022-QCYZH-036), Northwest
that in general, women have a lower thermoregulatory set point than University’s 2023 undergraduate talent training construction project
men, and women may store less heat than men (Bugyei-Twum, 2020; (202306), Northwest University’s 2023 graduate education compre-
Garcia et al., 2018). Furthermore, women during menstruation have a hensive reform research and practice project (202313).
different tolerance to heat stress than other periods due to fluctuating
hormone levels (Moiron et al., 2022; Stone et al., 2021). Additionally, CRediT authorship contribution statement
obesity population may be particularly vulnerable to high temperatures,
as the excess fat is not conducive to the dissipation of calories. Collec- ZZ, XPW, and ZZ collected relevant literature and drafted manu-
tively, heat stress is a complex physiological phenomenon, and scripts. MZS, QL, HDZ, ZYZS, WRL, ZW, and YY reviewed and made
comprehensive analysis of cross-talk between multiple factors not only significant revisions to the manuscript. ZZ, XPW, ZYZS, and WRL pre-
helps to improve the understanding of heat stress, but also provides pared figures and tables. YY and YSD guided the preparation of this
theoretical support for the personalized protection and treatment manuscript. All authors have read and approved the article.
strategies.
Epigenetic inheritance, a phenomenon in which gene sequences are Declaration of Generative AI and AI-assisted technologies in the
not altered but their expression is heritable, may be involved in the writing process
pathogenesis of heat stroke. Murray et al. showed that a single heat
stroke results in nearly 30,000 unique differentially methylated CpGs The authors declare that there is no use of Generative AI and/or
(DMCs) in monocytes of recovered female heatstroke mice, and epige- AIassisted technologies during the preparation of this work.
netic reprogramming increases significantly and becomes more robust
over time (Horowitz, 2021; Murray et al., 2021; Ren et al., 2019; Woods, Declaration of Competing Interest
2021). Importantly, alterations in epigenetic inheritance in leukocytes
through DMCs of NF-κB sequence-specific DNA-binding proteins leads to The authors declare that they have no known competing financial
a substantial increase in immunosuppression, exemplified by lost interests or personal relationships that could have appeared to influence
responsiveness to LPS-induced inflammation (Horowitz, 2021; Murray the work reported in this paper.
et al., 2021; Ren et al., 2019; Woods, 2021).
Notably, research has indicated that muscle genetics may play a role in Acknowledgements
heat stroke susceptibility for certain individuals. . This predisposition can
stem from either the presence of gene mutations similar to those observed None.
in malignant hyperthermia or from specific, unique genetic variations..
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