Curcumin Inhibits Renal Fibrosis by Suppressing S100A8/A9‐TLR4 Signaling via Gut Microbiota‐Derived Short‐Chain Fatty Acid in Macrophages

Renal fibrosis, a pivotal pathological process in chronic kidney disease (CKD), is closely associated with inflammatory responses and gut microbiota dysbiosis. Curcumin (CUR), a natural polyphenol derived from turmeric, shows anti-inflammatory and microbiota-modulating properties. However, its potential to attenuate renal fibrosis via gut microbiota-derived metabolites remains unclear. In this study, we investigated the mechanisms underlying the renoprotective effects of CUR, using a murine model of unilateral ureteral obstruction and LPS-stimulated bone marrow-derived macrophages (BMDMs). CUR treatment significantly alleviated renal interstitial fibrosis, reduced collagen deposition, and downregulated the pro-inflammatory mediators S100 calcium-binding proteins A8 (S100A8)/A9. Additionally, CUR modified the gut microbiota composition by enriching short-chain fatty acid (SCFA)-producing bacteria, leading to elevated systemic SCFA levels, particularly acetate, whose supplementation also ameliorated renal fibrosis, suppressed the S100A8/A9-toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF‑κB) signaling axis, and inhibited macrophage-myofibroblast transition (MMT). Acetate in vitro treatment attenuated the LPS-induced co-expression of S100A8/A9 and TLR4 in BMDMs, reduced pro-inflammatory cytokine release, and suppressed M1 polarization. These findings highlight that acetate, a key microbiota-derived metabolite increased by CUR treatment, mediates renal protection by targeting the S100A8/A9-TLR4 signaling pathway in macrophages, suggesting a novel gut-kidney axis-based therapeutic strategy for CKD.