https://doi.org/10.1016/j.apsb.2024.05.007

This new article publication from Acta Pharmaceutica Sinica B, discusses how heme oxygenase 1-mediated ferroptosis in Kupffer cells initiates liver injury during heat stroke.

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 stroke-induced 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-1β-mediated inflammation. Using single-cell RNA sequencing of murine macrophages, a distinct and highly susceptible Kupffer cell subtype, Clec4F⁺/CD206⁺, 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⁺/CD206⁺ subtype (KC2), activating phosphatidylinositol 4-kinase beta and promoting PI4P production. This cascade triggered NLRP3 inflammasome activation and maturation of IL-1β.

These findings underscore the critical role of targeted therapy against HMOX-1 in ferroptosis within Kupffer cells, particularly in Clec4F⁺/CD206⁺ 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.


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

Graphical Abstract: available at https://ars.els-cdn.com/content/image/1-s2.0-S2211383524001825-ga1_lrg.jpg
This study elucidates the intricate molecular mechanisms underpinning heat stroke-induced liver injury, highlighting the diverse responses of Kupffer cell (KC) subsets and the pivotal role of HMOX-1 in orchestrating ferroptosis in KCs, particularly in KC2, and NLRP3 inflammasome activation.
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The Journal of the Institute of Materia Medica, the Chinese Academy of Medical Sciences and the Chinese Pharmaceutical Association.
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CiteScore: 22.4
Impact Factor: 14.7 (Top 5 journal in the category of Pharmacology and pharmacy)
JIF without self-citation: 13.9
ISSN 2211-3835
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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, Heme oxygenase 1-mediated ferroptosis in Kupffer cells initiates liver injury during heat stroke,
Acta Pharmaceutica Sinica B, Volume 14, Issue 9, 2024, Pages 3983-4000, ISSN 2211-3835, https://doi.org/10.1016/j.apsb.2024.05.007