Sea cucumber peptides alleviate hyperuricemic nephropathy via HIF-1α/NF-κB/STAT3-SIRT1/p300 axis-mediated metabolic and epigenetic modulation.

Hyperuricemic nephropathy (HN) is a progressive kidney disease resulting from impaired urate metabolism, with limited effective therapies using natural sources. Sea cucumber peptides (SCPs) have shown metabolic regulatory potential in chronic diseases, but their efficacy in HN and underlying mechanisms remain unclear. This study investigated SCPs' effects using hyperuricemic mouse models and HK-2 cells. Interestingly, SCPs did not inhibit xanthine oxidase activity, yet significantly reduced serum uric acid (UA) levels, improved renal function, and attenuated pathological damage in mice. Mechanistically, SCPs reversed HN-induced metabolic reprogramming by downregulating key glycolytic enzymes (HK2, PFKFB3, and LDHA), reducing lactate accumulation, and enhancing ATP production. Multi-omics analyses revealed that SCPs optimized glycolysis-TCA cycle flux. Crucially, SCPs restored lactylation homeostasis via the SIRT1/p300 axis, suppressing global protein and histone lactylation. Concurrently, SCPs inhibited the HIF-1α/NF-κB/STAT3 pathway, decoupling metabolic-inflammatory signaling. These findings demonstrate that SCPs alleviate HN through multi-targeted regulation of urate metabolism, metabolic reprogramming, and lactylation, offering a novel strategy for functional food development.