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Effects of Extreme Heat Exposure on Heatstroke and Liver Injury in Mice: The Role of PPARα.

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Title: Effects of Extreme Heat Exposure on Heatstroke and Liver Injury in Mice: The Role of PPARα.
Authors: Guoqing Zhang1,2, Lisha Zhao1,3, Jiahui Wang1, Kunyi Wang1, Xiuyu Ji4,5, Renjie Hu1,3, Tong Hou1,3, Lu Zhang1,3, Ran Li1,3, Qinghua Sun1,3, Kezhong Zhang6, Cuiqing Liu1,3,7 liucuiqing@zcmu.edu.cn
Source: Environmental Health Perspectives. May2026, Vol. 134 Issue 1, p110-123. 14p.
Subject Terms: *Iron, *Extreme weather, *Animal experimentation, *Biomarkers, Liver injuries, Heat stroke, Oxygenases, Nonsteroidal anti-inflammatory agents, Iron in the body, Research funding, Body temperature regulation, Statistical hypothesis testing, T-test (Statistics), Data analysis, Polymerase chain reaction, Two-way analysis of variance, Cyclooxygenase 2, Descriptive statistics, Heat, Mice, Ferroptosis, Gene expression, Lipid peroxidation (Biology), Proteomics, Western immunoblotting, Statistics, One-way analysis of variance, Peroxisome proliferator-activated receptors, Collection & preservation of biological specimens, Comparative studies, Liver, Data analysis software, Liver function tests, Malondialdehyde, Disease complications, Chemical inhibitors
Abstract: BACKGROUND: Liver injury is a frequent complication of heatstroke and constitutes a direct cause of death. However, only a few studies examined the mechanism underlying heatstroke-induced liver injury. OBJECTIVE: We aimed to evaluate the role of peroxisome proliferator-activated receptor α (PPARα) in heatstroke-induced liver injury and to explore the potential mechanisms. METHODS: Male C57BL/6N mice were subjected to a control (22 ± 1 °C) or extreme heat temperature (39.5 ± 0.5 °C) to induce a heatstroke-associated liver injury animal model. PPARα agonist, ferroptosis inhibitor, and AAV8- mediated PPARα overexpression were administered to the mice to investigate the role of PPARα and ferroptosis in the heatstrokeinduced liver injury. Serum was collected for liver function evaluation. Liver tissues were applied for morphological observation, staining detection, ferroptosis examination, and mechanistic exploration. RESULTS: Compared with the control group, extreme heat exposure-induced temperature dysregulation, impaired liver function, and morphological damage in mice. Proteomics screened PPARα as a protein of interest, with its level being significantly decreased in response to extreme heat exposure. Both PPARα activation and overexpression attenuated extreme heat-induced heatstroke and liver injury. Hmox1 was next screened and higher Hmox1 expression was identified, accompanied by elevated markers of ferroptosis including prostaglandin-endoperoxide synthase 2 (Ptgs2), malondialdehyde (MDA), lipid peroxidation (LPO) and Fe2+ levels. Ferroptosis inhibition mitigated heatstroke and liver injury induced by heat exposure. In the setting of extreme heat exposure, PPARα activation suppressed Hmox1 expression and the levels of ferroptosis markers. It not only induced differences in the expression of members of iron generation, efflux and uptake process and reduced hepatic intracellular Fe2+ accumulation, but also stimulated expression of molecules for countering lipid peroxidation including Nrf2-SLC7A11-GPX4 axis and FSP1 signaling. DISCUSSION: PPARα played an essential role in extreme heat exposure-induced heatstroke and liver injury, and PPARα intervention conferred protection against it via inhibition of ferroptosis. [ABSTRACT FROM AUTHOR]
Copyright of Environmental Health Perspectives is the property of National Institute of Environmental Health Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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Items – Name: Title
  Label: Title
  Group: Ti
  Data: Effects of Extreme Heat Exposure on Heatstroke and Liver Injury in Mice: The Role of PPARα.
– Name: Author
  Label: Authors
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  Data: <searchLink fieldCode="AR" term="%22Guoqing+Zhang%22">Guoqing Zhang</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Lisha+Zhao%22">Lisha Zhao</searchLink><relatesTo>1,3</relatesTo><br /><searchLink fieldCode="AR" term="%22Jiahui+Wang%22">Jiahui Wang</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Kunyi+Wang%22">Kunyi Wang</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Xiuyu+Ji%22">Xiuyu Ji</searchLink><relatesTo>4,5</relatesTo><br /><searchLink fieldCode="AR" term="%22Renjie+Hu%22">Renjie Hu</searchLink><relatesTo>1,3</relatesTo><br /><searchLink fieldCode="AR" term="%22Tong+Hou%22">Tong Hou</searchLink><relatesTo>1,3</relatesTo><br /><searchLink fieldCode="AR" term="%22Lu+Zhang%22">Lu Zhang</searchLink><relatesTo>1,3</relatesTo><br /><searchLink fieldCode="AR" term="%22Ran+Li%22">Ran Li</searchLink><relatesTo>1,3</relatesTo><br /><searchLink fieldCode="AR" term="%22Qinghua+Sun%22">Qinghua Sun</searchLink><relatesTo>1,3</relatesTo><br /><searchLink fieldCode="AR" term="%22Kezhong+Zhang%22">Kezhong Zhang</searchLink><relatesTo>6</relatesTo><br /><searchLink fieldCode="AR" term="%22Cuiqing+Liu%22">Cuiqing Liu</searchLink><relatesTo>1,3,7</relatesTo><i> liucuiqing@zcmu.edu.cn</i>
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  Data: <searchLink fieldCode="JN" term="%22Environmental+Health+Perspectives%22">Environmental Health Perspectives</searchLink>. May2026, Vol. 134 Issue 1, p110-123. 14p.
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  Data: *<searchLink fieldCode="DE" term="%22Iron%22">Iron</searchLink><br />*<searchLink fieldCode="DE" term="%22Extreme+weather%22">Extreme weather</searchLink><br />*<searchLink fieldCode="DE" term="%22Animal+experimentation%22">Animal experimentation</searchLink><br />*<searchLink fieldCode="DE" term="%22Biomarkers%22">Biomarkers</searchLink><br /><searchLink fieldCode="DE" term="%22Liver+injuries%22">Liver injuries</searchLink><br /><searchLink fieldCode="DE" term="%22Heat+stroke%22">Heat stroke</searchLink><br /><searchLink fieldCode="DE" term="%22Oxygenases%22">Oxygenases</searchLink><br /><searchLink fieldCode="DE" term="%22Nonsteroidal+anti-inflammatory+agents%22">Nonsteroidal anti-inflammatory agents</searchLink><br /><searchLink fieldCode="DE" term="%22Iron+in+the+body%22">Iron in the body</searchLink><br /><searchLink fieldCode="DE" term="%22Research+funding%22">Research funding</searchLink><br /><searchLink fieldCode="DE" term="%22Body+temperature+regulation%22">Body temperature regulation</searchLink><br /><searchLink fieldCode="DE" term="%22Statistical+hypothesis+testing%22">Statistical hypothesis testing</searchLink><br /><searchLink fieldCode="DE" term="%22T-test+%28Statistics%29%22">T-test (Statistics)</searchLink><br /><searchLink fieldCode="DE" term="%22Data+analysis%22">Data analysis</searchLink><br /><searchLink fieldCode="DE" term="%22Polymerase+chain+reaction%22">Polymerase chain reaction</searchLink><br /><searchLink fieldCode="DE" term="%22Two-way+analysis+of+variance%22">Two-way analysis of variance</searchLink><br /><searchLink fieldCode="DE" term="%22Cyclooxygenase+2%22">Cyclooxygenase 2</searchLink><br /><searchLink fieldCode="DE" term="%22Descriptive+statistics%22">Descriptive statistics</searchLink><br /><searchLink fieldCode="DE" term="%22Heat%22">Heat</searchLink><br /><searchLink fieldCode="DE" term="%22Mice%22">Mice</searchLink><br /><searchLink fieldCode="DE" term="%22Ferroptosis%22">Ferroptosis</searchLink><br /><searchLink fieldCode="DE" term="%22Gene+expression%22">Gene expression</searchLink><br /><searchLink fieldCode="DE" term="%22Lipid+peroxidation+%28Biology%29%22">Lipid peroxidation (Biology)</searchLink><br /><searchLink fieldCode="DE" term="%22Proteomics%22">Proteomics</searchLink><br /><searchLink fieldCode="DE" term="%22Western+immunoblotting%22">Western immunoblotting</searchLink><br /><searchLink fieldCode="DE" term="%22Statistics%22">Statistics</searchLink><br /><searchLink fieldCode="DE" term="%22One-way+analysis+of+variance%22">One-way analysis of variance</searchLink><br /><searchLink fieldCode="DE" term="%22Peroxisome+proliferator-activated+receptors%22">Peroxisome proliferator-activated receptors</searchLink><br /><searchLink fieldCode="DE" term="%22Collection+%26+preservation+of+biological+specimens%22">Collection & preservation of biological specimens</searchLink><br /><searchLink fieldCode="DE" term="%22Comparative+studies%22">Comparative studies</searchLink><br /><searchLink fieldCode="DE" term="%22Liver%22">Liver</searchLink><br /><searchLink fieldCode="DE" term="%22Data+analysis+software%22">Data analysis software</searchLink><br /><searchLink fieldCode="DE" term="%22Liver+function+tests%22">Liver function tests</searchLink><br /><searchLink fieldCode="DE" term="%22Malondialdehyde%22">Malondialdehyde</searchLink><br /><searchLink fieldCode="DE" term="%22Disease+complications%22">Disease complications</searchLink><br /><searchLink fieldCode="DE" term="%22Chemical+inhibitors%22">Chemical inhibitors</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: BACKGROUND: Liver injury is a frequent complication of heatstroke and constitutes a direct cause of death. However, only a few studies examined the mechanism underlying heatstroke-induced liver injury. OBJECTIVE: We aimed to evaluate the role of peroxisome proliferator-activated receptor α (PPARα) in heatstroke-induced liver injury and to explore the potential mechanisms. METHODS: Male C57BL/6N mice were subjected to a control (22 ± 1 °C) or extreme heat temperature (39.5 ± 0.5 °C) to induce a heatstroke-associated liver injury animal model. PPARα agonist, ferroptosis inhibitor, and AAV8- mediated PPARα overexpression were administered to the mice to investigate the role of PPARα and ferroptosis in the heatstrokeinduced liver injury. Serum was collected for liver function evaluation. Liver tissues were applied for morphological observation, staining detection, ferroptosis examination, and mechanistic exploration. RESULTS: Compared with the control group, extreme heat exposure-induced temperature dysregulation, impaired liver function, and morphological damage in mice. Proteomics screened PPARα as a protein of interest, with its level being significantly decreased in response to extreme heat exposure. Both PPARα activation and overexpression attenuated extreme heat-induced heatstroke and liver injury. Hmox1 was next screened and higher Hmox1 expression was identified, accompanied by elevated markers of ferroptosis including prostaglandin-endoperoxide synthase 2 (Ptgs2), malondialdehyde (MDA), lipid peroxidation (LPO) and Fe2+ levels. Ferroptosis inhibition mitigated heatstroke and liver injury induced by heat exposure. In the setting of extreme heat exposure, PPARα activation suppressed Hmox1 expression and the levels of ferroptosis markers. It not only induced differences in the expression of members of iron generation, efflux and uptake process and reduced hepatic intracellular Fe2+ accumulation, but also stimulated expression of molecules for countering lipid peroxidation including Nrf2-SLC7A11-GPX4 axis and FSP1 signaling. DISCUSSION: PPARα played an essential role in extreme heat exposure-induced heatstroke and liver injury, and PPARα intervention conferred protection against it via inhibition of ferroptosis. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Environmental Health Perspectives is the property of National Institute of Environmental Health Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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RecordInfo BibRecord:
  BibEntity:
    Identifiers:
      – Type: doi
        Value: 10.1021/EHP.6c00267
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      – Code: eng
        Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 14
        StartPage: 110
    Subjects:
      – SubjectFull: Iron
        Type: general
      – SubjectFull: Extreme weather
        Type: general
      – SubjectFull: Animal experimentation
        Type: general
      – SubjectFull: Biomarkers
        Type: general
      – SubjectFull: Liver injuries
        Type: general
      – SubjectFull: Heat stroke
        Type: general
      – SubjectFull: Oxygenases
        Type: general
      – SubjectFull: Nonsteroidal anti-inflammatory agents
        Type: general
      – SubjectFull: Iron in the body
        Type: general
      – SubjectFull: Research funding
        Type: general
      – SubjectFull: Body temperature regulation
        Type: general
      – SubjectFull: Statistical hypothesis testing
        Type: general
      – SubjectFull: T-test (Statistics)
        Type: general
      – SubjectFull: Data analysis
        Type: general
      – SubjectFull: Polymerase chain reaction
        Type: general
      – SubjectFull: Two-way analysis of variance
        Type: general
      – SubjectFull: Cyclooxygenase 2
        Type: general
      – SubjectFull: Descriptive statistics
        Type: general
      – SubjectFull: Heat
        Type: general
      – SubjectFull: Mice
        Type: general
      – SubjectFull: Ferroptosis
        Type: general
      – SubjectFull: Gene expression
        Type: general
      – SubjectFull: Lipid peroxidation (Biology)
        Type: general
      – SubjectFull: Proteomics
        Type: general
      – SubjectFull: Western immunoblotting
        Type: general
      – SubjectFull: Statistics
        Type: general
      – SubjectFull: One-way analysis of variance
        Type: general
      – SubjectFull: Peroxisome proliferator-activated receptors
        Type: general
      – SubjectFull: Collection & preservation of biological specimens
        Type: general
      – SubjectFull: Comparative studies
        Type: general
      – SubjectFull: Liver
        Type: general
      – SubjectFull: Data analysis software
        Type: general
      – SubjectFull: Liver function tests
        Type: general
      – SubjectFull: Malondialdehyde
        Type: general
      – SubjectFull: Disease complications
        Type: general
      – SubjectFull: Chemical inhibitors
        Type: general
    Titles:
      – TitleFull: Effects of Extreme Heat Exposure on Heatstroke and Liver Injury in Mice: The Role of PPARα.
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            – D: 01
              M: 05
              Text: May2026
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