FABP5 drives silica-induced myofibroblast senescence and pulmonary fibrosis through a FASN/UCP2 metabolic-mitochondrial axis.

Silicosis is a devastating occupational lung disease driven by chronic oxidative stress and the persistent accumulation of senescent cells. However, the metabolic mechanisms underlying silica-induced senescence and subsequent fibrotic remodeling remain elusive. Here, we identify fatty acid binding protein 5 (FABP5) as a central metabolic driver of silica-induced myofibroblast senescence. Intracellularly, FABP5 interacts with and shields fatty acid synthase (FASN) from ubiquitin-proteasomal degradation, disrupting lipid homeostasis and causing uncoupling protein 2 (UCP2)-dependent mitochondrial dysfunction and cellular senescence. Extracellularly, senescent fibroblasts secrete FABP5 as an unconventional senescence-associated secretory phenotype (SASP) factor. This secreted FABP5 activates β-catenin signaling, creating a paracrine feed-forward loop that drives the activation of neighboring quiescent fibroblasts. Therapeutically, systemic silencing of FABP5 using lipid nanoparticles (siFabp5-LNPs) robustly attenuates cellular senescence, metabolic disruption, and fibrotic remodeling in young and aged mouse models of pulmonary fibrosis induced by silica dust. Collectively, our findings uncover a previously unrecognized FABP5/FASN/UCP2 metabolic-redox axis that drives stress-induced senescence. By linking intracellular mitochondrial dysfunction with extracellular pro-fibrotic signaling, FABP5 emerges as a highly promising therapeutic target and potential biomarker for silicosis and other oxidative stress-driven fibrotic diseases.