Protective effects of 17β-Estradiol (E(2)) against macrophage ferroptosis via tubular epithelial cells derived exosomal HDAC2 mediated H3K27 deacetylation at the GPX4 promoter during sepsis-induced renal injury

作者：Shu L, Yi X, Zheng G, Tan H, Li Y, Li X, Chen L · 发表于：Archives of biochemistry and biophysics · 年份：2026 · DOI：10.1016/j.abb.2026.110950 · 研究领域：Histone Deacetylase 2、Sepsis、Ferroptosis、Acute Kidney Injury、Macrophages、Estradiol、Exosomes、Phospholipid Hydroperoxide Glutathione Peroxidase、Histones、Animals、Mice、Humans

Ferroptosis represents a regulated form of cell death. Currently, the impact of ferroptosis on sepsis-induced acute kidney injury (SAKI) remains unexplored. We examined the effect of 17β-estradiol (E2) on macrophage inflammation and ferroptosis in SAKI. Histological staining of renal sections was conducted in CLP mice. Levels of serum creatinine (Scr) and blood urea nitrogen (BUN) were detected by kits. Levels of TNF-α, IL-1β and IL-6 were measured by ELISA. HK-2 cells with different treatments were co-cultured with PMA-induced THP-1 cells (M0 macrophages). CCK-8 and flow cytometry detected cell viability and apoptosis. MDA, GSH and Fe2+ levels were detected by kits. Expressions of HDAC2, HDAC5 and GPX4 were detected by RT-qPCR. Western blot assessed protein levels of HDAC2, GPX4, ACSL4 and exosome markers (CD63, TSG101). Exosomes from HK-2 cells were identified using electron microscope and particle size analysis. The target relationships were confirmed through ChIP and luciferase reporter assays. E2 protected against CLP-induced kidney damage and decreased ferroptosis in SAKI mice. E2 effectively mitigated LPS-induced damage in HK-2 cells and reduced HDAC2 expression. Exosomal HDAC2 from HK-2 cells induced macrophage inflammation and ferroptosis. Exosomal HDAC2 impedes GPX4 expression in macrophages by aiding HDAC2-driven H3K27 deacetylation at GPX4 promoter. Exosomes from HK-2 cells with increased HDAC2 levels overturned renal protective benefits of E2 in septic AKI mice. ...