FABP1 ‐Mediated Lipid Metabolic Reprogramming Buffers Lipotoxicity in Nephrolithiasis via Maintaining PPARγ Activity

ABSTRACT Nephrolithiasis‐induced lipotoxicity is a critical driver of tubular cell death and renal function decline, yet targeted pharmacological interventions remain a major unmet clinical need. While Fatty Acid‐Binding Protein 1 (FABP1) is widely recognized as a passive injury biomarker, its active functional role in buffering lipotoxicity during nephrolithiasis remains uncharacterized. By integrating clinical specimens from nephrolithiasis patients, AAV9‐mediated kidney‐specific Fabp1 knockdown murine models, and HK‐2 cell lines, we delineated the FABP1 regulatory landscape using transcriptomic and untargeted metabolomic profiling. Furthermore, the core mechanistic interactions were definitively validated via Co‐Immunoprecipitation (Co‐IP) and PPRE‐driven dual‐luciferase reporter assays. FABP1 is significantly upregulated in nephrolithiasis. Mechanistically, crystal‐induced lysosomal stress triggers Ca 2+ efflux, which activates the calcineurin pathway to drive TFEB nuclear translocation and subsequent FABP1 transcription. Crucially, FABP1 functions as an indispensable nuclear chaperone, physically engaging PPARγ to sustain its core transcriptional activity. FABP1 deficiency dismantles this defense, impairing protective lipid droplet biogenesis to sequester free fatty acids. This failure precipitates excessive 4‐HNE accumulation, marked lipid peroxidation, TCA cycle collapse, a pronounced NF‐κB‐driven inflammatory storm, and ultimate renal functional deterioration. Importantly, targeted pharmacological activation of PPARγ utilizing rosiglitazone circumvents FABP1 depletion, rewiring global lipid and energetic fluxes to rescue tubular cell injury. Our findings redefine FABP1 from a passive clinical biomarker to an active homeostatic buffer. This study delineates the Ca 2+ /calcineurin‐TFEB‐FABP1‐PPARγ axis as a vital defense mechanism against lipotoxicity, providing a compelling translational rationale for PPARγ‐targeted metabolic interventions to treat nephrolithiasis.