Daohui Gong,Xueping Liu,Pengfei Wu,Yue Chen,Yuhang Xu,Zhan Gao,Hang Qian,Guansong Wang,Binfeng He
Macrophage dysfunction is a significant contributor to more than 70 % of sepsis-related deaths, specifically secondary bacterial infections, during the immunosuppression stage of sepsis. Nevertheless, the role of Rab26 in this context remains unclear. In this study, we observed a substantial decrease in Rab26 expression in macrophages during the immunosuppressive phase of sepsis, which was also found to be suppressed by high extracellular levels of HMGB1 . During the progression of sepsis, Rab26 deficiency promotes a polarization shift from the M1 to the M2-like phenotype in macrophages, rendering them susceptible to ferroptosis . Subsequent experimentation has revealed that Rab26 deficiency facilitates the degradation of GPX4, thereby aggravating macrophage ferroptosis through the upregulation of levels of lipid ROS , MDA , and ferrous iron induced by RSL3, a ferroptosis inducer. Additionally, Rab26-deficient mice in the immunosuppressed phase of sepsis exhibit heightened susceptibility to secondary infections, leading to exacerbated lung tissue damage and increased mortality rate. Overall, these findings indicate that Rab26 plays a crucial role in sepsis-induced macrophage immunosuppression by regulating macrophage ferroptosis and polarization. Hence, it represents a potential novel target for sepsis therapy.
Macrophage ferroptosis contributes to sepsis-associated acute lung injury (ALI); however, its upstream regulatory mechanisms remain poorly understood. Here, using a cecal ligation and puncture (CLP) murine sepsis model, we observed that macrophages from septic mice and bone marrow-derived macrophages (BMDMs) exposed to septic bronchoalveolar lavage fluid (BALF) exhibited concurrent suppression of EPOR expression and induction of ferroptosis. EPOR deficiency selectively reduced basal GPX4 expression and amplified ferroptotic cell death upon challenge with RSL3 or septic BALF. EPOR M−/− mice showed exacerbated sepsis-induced lung injury and mortality, which were rescued by the ferroptosis inhibitor ferrostatin-1 (Fer-1). Mechanistically, EPOR deficiency downregulated PPARγ, which promotes GPX4 expression. EPOR deficiency also impaired PINK1-mediated mitophagy by reducing PINK1 but not PARKIN levels, while mitophagy induction attenuated ferroptosis in EPOR-deficient cells. rhEPO stimulation enhanced the EPOR/PPARγ axis and suppressed lipid peroxidation, whereas PPARγ antagonism inhibited PINK1 expression. We further identified Rab26 as a critical stabilizer of EPOR. Specifically, Rab26 deficiency upregulated the expression of BTRC, an E3 ligase that interacts with EPOR to promote its degradation. Consequently, Rab26 deficiency decreased EPOR levels, subsequently suppressing PPARγ and PINK1, thereby reducing GPX4 expression and blunting rhEPO-induced PINK1 upregulation. Collectively, EPOR signaling protects macrophages from ferroptosis by activating PINK1-mediated mitophagy in a Rab26-dependent manner. The Rab26-EPOR-PPARγ axis represents a promising therapeutic target for sepsis-induced lung injury.
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