Heme oxygenase 1-mediated ferroptosis in Kupffer cells initiates liver injury during heat stroke  

作　　者：Ru Li Riqing Wei Chenxin Liu Keying Zhang Sixiao He Zhifeng Liu Junhao Huang Youyong Tang Qiyuan An Ligen Lin Lishe Gan Liying Zhao Xiaoming Zou Fudi Wang Yuan Ping Qiang Ma 

机构地区：[1]The Seventh Affiliated Hospital,Southern Medical University,Foshan 528244,China [2]Department of Biopharmaceutics,School of Laboratory Medicine and Biotechnology,Southern Medical University,Guangzhou 510000,China [3]Medical Critical Care Medicine,General Hospital of Southern Theatre Command of PLA,Guangzhou 510000,China [4]Guangdong Branch Center,National Clinical Research Center for Geriatric Diseases(Chinese PLA General Hospital),Guangzhou 510000,China [5]State Key Laboratory of Quality Research in Chinese Medicine,Institute of Chinese Medical Sciences,University of Macao,Avenida da Universidade,Taip1,Macao 999078,China [6]School of Pharmaceutical Sciences,Zhejiang Chinese Medical University,Hangzhou 311402,China [7]Department of General Surgery,Nanfang Hospital,the First School of Clinical Medicine,Southern Medical University,Guangzhou 510000,China [8]The Fourth Affiliated Hospital,the First Affiliated Hospital,School of Public Health,Institute of Translational Medicine,Cancer Center,State Key Laboratory of Experimental Hematology,Zhejiang University School of Medicine,Hangzhou 310000,China [9]The First Affiliated Hospital,the Second Affiliated Hospital,Basic Medical Sciences,School of Public Health,Hengyang Medical School,University of South China,Hengyang 421200,China [10]College of Pharmaceutical Sciences,Zhejiang University,Hangzhou 310000,China [11]Liangzhu Laboratory,Zhejiang University Medical Center,Hangzhou 310000,China [12]Guangdong Provincial Key Laboratory of Immune Regulation and Immunotherapy,School of Laboratory Medicine and Biotechnology,Southern Medical University,Guangzhou 510000,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第9期3983-4000,共18页药学学报（英文版）

基　　金：the following funding sources:the National Natural Science Foundation of China(82072100 to Qiang Ma and 82172814 to Liying Zhao);the Natural Science Foundation of Shenzhen(JCYJ20210324120212033,China);Guangdong Provincial Key Laboratory of Immune Regulation and Immunotherapy,School of Laboratory Medicine and Biotechnology,Southern Medical University(2022B1212010009,China).

摘　　要：With the escalating prevalence of global heat waves,heat stroke has become a prominent health concern,leading to substantial liver damage.Unlike other forms of liver injury,heat strokeinduced damage is characterized by heat cytotoxicity and heightened inflammation,directly contributing to elevated mortality rates.While clinical assessments have identified elevated bilirubin levels as indicative of Kupffer cell dysfunction,their specific correlation with heat stroke liver injury remains unclear.Our hypothesis proposes the involvement of Kupffer cell ferroptosis during heat stroke,initiating IL-1bmediated inflammation.Using single-cell RNA sequencing of murine macrophages,a distinct and highly susceptible Kupffer cell subtype,Clec4Ft/CD206t,emerged,with heme oxygenase 1(HMOX-1)playing a pivotal role.Mechanistically,heat-induced HMOX-1,regulated by early growth response factor 1,mediated ferroptosis in Kupffer cells,specifically in the Clec4F t/CD206 t subtype(KC2),activating phosphatidylinositol 4-kinase beta and promoting PI4P production.This cascade triggered NLRP3 inflammasome activation and maturation of IL-1b.These findings underscore the critical role of targeted therapy against HMOX-1 in ferroptosis within Kupffer cells,particularly in Clec4F t/CD206 t KCs.Such an approach has the potential to mitigate inflammation and alleviate acute liver injury in the context of heat stroke,offering a promising avenue for future therapeutic interventions.

关 键 词：Heat stroke Liver injury Kupffer cells Ferroptosis Heme oxygenase 1 Phosphatidylinositol 4-kinase beta NLRP3 Early growth response factor 1 

分 类 号：R575[医药卫生—消化系统]