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Updated: Oct 8, 2026
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TMEM16F deficiency alleviates sepsis-induced acute lung injury through regulating macrophage polarization
Meishan Yan1,2, Caixu Liu1,2, Xu Han1,2
1Department of Medical Laboratory Science and Technology, Harbin Medical University-Daqing, Daqing, China.
Background:
Sepsis-induced acute lung injury (ALI) is closely associated with the balance of M1/M2 macrophage polarization and excessive inflammation. Recently studies have revealed that TMEM16F, a calcium-activated phospholipid scramblase, participates in modulating inflammatory response and oxidative stress. However, the effect of TMEM16F on regulation of M1/M2 polarization during sepsis-induced ALI and its underlying mechanisms remain unclear.
Methods:
In the present study, we utilized septic patients, lipopolysaccharide (LPS)-induced ALI mouse models, and LPS-treated mouse alveolar macrophages (AMs) as well as human THP-1-derived macrophages to investigate the potential functions and molecular mechanisms of TMEM16F in sepsis-induced ALI.
Results:
Our clinical analysis showed that TMEM16F mRNA levels in peripheral blood mononuclear cells (PBMCs) were positively correlated with inflammation and disease severity in septic patients. Additionally, TMEM16F was highly expressed in LPS-treated THP-1 macrophages and in vitro sepsis-induced ALI models. TMEM16F knockout significantly promoted M2 macrophage polarization, alleviated systemic inflammation, lung injury, oxidative stress and microthrombosis, and improved survival in septic mice. Mechanistically, TMEM16F could interact with SOCS3, suppressing downstream STAT3 signaling pathway and promoting NLRP3 inflammasome activation, resulting in increased M1 polarization and inflammatory response. Moreover, we identified platycodin D (PLD), a saponin found from Platycodon grandiflorum, could be an effective inhibitor of TMEM16F, and ameliorate sepsis-induced ALI by reprogramming macrophages towards an anti-inflammatory phenotype via inhibiting TMEM16F-mediated SOCS3/STAT3/NLRP3 pathway.
Conclusions:
Collectively, these findings indicated that TMEM16F plays a crucial role in regulating macrophage phenotypic switching, and highlighted targeting TMEM16F is a therapeutic strategy for attenuating sepsis-associated ALI through immune homeostasis restoration.
