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While Fatty Acid\u2010Binding 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\u2010mediated kidney\u2010specific Fabp1 knockdown murine models, and HK\u20102 cell lines, we delineated the FABP1 regulatory landscape using transcriptomic and untargeted metabolomic profiling. Furthermore, the core mechanistic interactions were definitively validated via Co\u2010Immunoprecipitation (Co\u2010IP) and PPRE\u2010driven dual\u2010luciferase reporter assays. FABP1 is significantly upregulated in nephrolithiasis. Mechanistically, crystal\u2010induced lysosomal stress triggers Ca\n                    <jats:sup>2+<\/jats:sup>\n                    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 PPAR\u03b3 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\u2010HNE accumulation, marked lipid peroxidation, TCA cycle collapse, a pronounced NF\u2010\u03baB\u2010driven inflammatory storm, and ultimate renal functional deterioration. Importantly, targeted pharmacological activation of PPAR\u03b3 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\n                    <jats:sup>2+<\/jats:sup>\n                    \/calcineurin\u2010TFEB\u2010FABP1\u2010PPAR\u03b3 axis as a vital defense mechanism against lipotoxicity, providing a compelling translational rationale for PPAR\u03b3\u2010targeted metabolic interventions to treat nephrolithiasis.\n                  <\/jats:p>","DOI":"10.1096\/fj.202602800rr","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T10:29:38Z","timestamp":1789727378000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>FABP1<\/scp>\n                    \u2010Mediated Lipid Metabolic Reprogramming Buffers Lipotoxicity in Nephrolithiasis via Maintaining\n                    <scp>PPAR\u03b3<\/scp>\n                    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