Inhibiting lactylation for efficient treatment of renal fibrosis through targeting nanomedicine of renal lactate accumulation in obstructed kidney.

Chronic kidney disease (CKD) is a major global public health issue, with a prevalence that continues to rise. However, effective therapeutic approaches are still lacking. Tubulointerstitial fibrosis (TIF) is a key pathological process in CKD progression, regulated by the metabolism and epigenetics axis. In CKD, local renal hypoxia induces metabolic reprogramming, leading to excessive lactate accumulation. The accumulated lactate not only acts as a metabolite, but also acts as an epigenetic regulatory signal to drive the expression of pro-fibrotic genes through histone lactylation modification. In this process, lactate dehydrogenase A (LDHA), as the core rate-limiting enzyme of this axis, has emerged as a promising therapeutic target. Stiripentol (STP), a drug approved by the European Medicines Agency for the treatment of refractory epilepsy, is the most studied LDHA inhibitor. However, it suffers from off-target effects, low aqueous solubility, and instability in acidic environments. To address these issues, in this study, for the first time, a nano-liposome drug delivery system based on LTH modification (L/STP/Lipo) was constructed to achieve kidney-targeted delivery of STP. LTH is a peptide that binds to kidney injury molecule-1 (KIM-1), a biomarker protein expressed on injured tubular cells. In both in vitro and in vivo studies, L/STP/Lipo effectively accumulated in injured renal tubular cells, blocked lactate production by inhibiting LDHA activity, reduced lactylation levels, and interfered with the transforming growth factor-β1 (TGF-β1)/small mothers against decapentaplegic (Smad) signaling pathway, eventually inhibiting renal tubular epithelial-mesenchymal transition (EMT) and effectively slowing TIF progression. This study has opened a new avenue for targeted CKD therapy.