H3K18 lactylation-mediated SPHK1-SIRT1 feedback loop accelerates pyroptosis of tubular epithelial cells in sepsis-associated acute kidney injury

Background: Lactate accumulation exacerbates the severity of sepsis-associated acute kidney injury (SA-AKI), although the mechanism remains unclear. Since pyroptosis contributes to renal tubular epithelial cell (RTEC) death during SA-AKI, this study explores whether lactate exacerbates pathogenesis by promoting RTEC pyroptosis. Methods: . Results: and PF-543 synergistically attenuated SA-AKI. Sepsis-induced lactate accumulation promoted P300-mediated histone H3 lysine 18 lactylation (H3K18la) at the SPHK1 promoter, epigenetically enhancing its transcription. SPHK1 then phosphorylated and degraded SIRT1, inducing peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α) hyperacetylation, thereby impairing SIRT1/PGC-1α signaling and triggering NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-driven pyroptosis. Reciprocally, SIRT1 acted as a delactylase delactylase to reduce H3K18la and inhibit SPHK1 transcription, forming a SPHK1-SIRT1 negative feedback loop. Conclusions: supplementation and SPHK1 inhibition represents a promising therapeutic strategy for SA-AKI.