Activation of autophagy with PF-06409577 alleviates heatstroke-induced organ injury

Wei Zhang; Huajing Zeng; Siyu Xie; Cheng Yu; Meina Zhang; Qiuyan Chen; Huiyue Dong; Hui Zhang; Hao Lin; Nengjing Zheng; Lin Zhu; Jun Lu

doi:10.1016/j.envint.2025.109285

Activation of autophagy with PF-06409577 alleviates heatstroke-induced organ injury

Environ Int. 2025 Jan 19:196:109285. doi: 10.1016/j.envint.2025.109285. Online ahead of print.

Authors

Wei Zhang¹, Huajing Zeng², Siyu Xie³, Cheng Yu³, Meina Zhang³, Qiuyan Chen³, Huiyue Dong³, Hui Zhang³, Hao Lin², Nengjing Zheng¹, Lin Zhu³, Jun Lu⁴

Affiliations

¹ Fujian Provincial Key Laboratory of Transplant Biology, Fuzong Teaching Hospital (900th Hospital of Joint Logistic Support Force), Fujian University of Traditional Chinese Medicine, Fuzhou 350025, China.
² Laboratory of Basic Medicine, Fuzong Clinical Medical College of Fujian Medical University, Fuzhou 350025, China.
³ Fujian Provincial Key Laboratory of Transplant Biology, Fuzong Teaching Hospital (900th Hospital of Joint Logistic Support Force), Fujian University of Traditional Chinese Medicine, Fuzhou 350025, China; Laboratory of Basic Medicine, Fuzong Clinical Medical College of Fujian Medical University, Fuzhou 350025, China; Dongfang Hospital, Xiamen University, Fuzhou 350025, China.
⁴ Fujian Provincial Key Laboratory of Transplant Biology, Fuzong Teaching Hospital (900th Hospital of Joint Logistic Support Force), Fujian University of Traditional Chinese Medicine, Fuzhou 350025, China; Laboratory of Basic Medicine, Fuzong Clinical Medical College of Fujian Medical University, Fuzhou 350025, China; Dongfang Hospital, Xiamen University, Fuzhou 350025, China; Organ Transplant Institute, 900th Hospital of Joint Logistic Support Force, Fuzhou 350025, China. Electronic address: junlu.heather@xmu.edu.cn.

PMID: 39855028
DOI: 10.1016/j.envint.2025.109285

Abstract

Heat waves are a significant environmental issue threatening global human health. Extreme temperatures can lead to various heat-related illnesses, with heatstroke being among the most severe. Currently, there are no effective treatments to mitigate the multi-organ damage caused by heatstroke. We found that heat stress activated autophagy. Knockdown of the autophagy-related gene 7 (ATG7) or knockout of the autophagy initiation regulatory genes UNC-51-like autophagy activating kinase 1/2 (ULK1/ULK2) increased cell death. PF-06409577, an allosteric activator of AMP-activated protein kinase β (AMPKβ), reduced heat stress-induced cell death by promoting autophagy. Inhibition of ATG7 or ULK1 weakened PF-06409577's protective effect on cells. Treatment of heatstroke mouse models with PF-06409577 suppressed high temperature-induced damage to multiple organs, including the liver, kidneys, lungs, and small intestine. PF-06409577 protected liver and kidney functions, lowered the expression of kidney injury markers neutrophil gelatinase associated lipocalin (Ngal), secreted phosphoprotein 1 (Spp1), and clusterin (Clu), and reduced levels of the inflammatory factor IL-6. Additionally, it decreased heat stress-induced macrophage infiltration and IL-6 production in the liver. The results indicate that activation of autophagy serves a protective function during heat stress, and the AMPK activator PF-06409577 exhibits potential in mitigating heatstroke-induced multi-organ damage through its ability to promote autophagy.

Keywords: Autophagy; Cell death; Heatstroke; Organ damage; PF-06409577.