Curcumin Alleviates Sepsis-Associated Acute Kidney Injury Potentially by Inhibiting Ferroptosis Through the ACSL4/GPX4 Signaling Pathway

This study aimed to investigate the protective effect of curcumin against sepsis-associated acute kidney injury (SA-AKI) in vitro and in vivo, and to clarify the role of Ferroptosis in this protection. Human renal tubular epithelial cell (RTEC) line HK-2 was stimulated with lipopolysaccharide (LPS). Ferroptosis was further induced with erastin. In vivo, a rat SA-AKI model was produced by cecal ligation and puncture (CLP) and allocated to the Sham, sepsis, and curcumin (Cur) + sepsis (Sep) groups. Glutathione (GSH), malondialdehyde (MDA), and pro-inflammatory cytokines were quantified by ELISA. Western blot analysis was used to evaluate the ferroptosis-related proteins, including long-chain acyl-coenzyme synthetases 4 (ACSL4) and Glutathione Peroxidase 4 (GPX4). Apoptosis of RTECs was assessed with TUNEL staining, and ultrastructural changes were examined by transmission electron microscopy (TEM). Compared with the Sepsis group, the Cur + Sep group showed significantly lower Paller damage scores, reduced Scr, BUN, TNF-α, IL-1β, IL-6, MDA, Fe²⁺ levels, and ACSL4 protein expression (all p < 0.05). Conversely, GSH and GPX4 levels were significantly elevated in the Cur + Sep group (both p < 0.05). TUNEL staining revealed fewer apoptotic RTECs in the Cur + Sep group compared with the Sepsis group (p < 0.05). TEM demonstrated swollen mitochondria with condensed membranes and vanished cristae in the sepsis group, changes that were markedly alleviated by curcumin. In HK-2 cells, erastin abolished curcumin's protective effect against LPS-induced injury. Curcumin attenuates SA-AKI, likely by suppressing inflammation and Ferroptosis via the ACSL4/GPX4 signaling pathway.

ACSL4/GPX4 axis; acute kidney injury; curcumin; ferroptosis; renal tubular epithelial cell; sepsis.