PEX5 integrates the p38 MAPK signaling pathway and taurine metabolism to regulate senescence in lung fibroblasts.

Abstract

Chronic lung diseases are a growing global health burden in aging populations, yet their underlying mechanisms remain poorly defined, and current treatment options are limited. Cellular senescence, a hallmark of aging, is increasingly recognized as a key driver of chronic lung pathology and is often accompanied by dysfunction in subcellular organelles. Among these, peroxisomes have emerged as important regulators, though their specific roles in senescence remain underexplored. To address this gap, we investigated the function of peroxisomes during replicative and oxidative stress-induced senescence in human fetal lung fibroblasts (HFL-1). We found that peroxisomal biogenesis, including the import receptor PEX5 expression, is significantly downregulated in senescent cells. Loss of PEX5 activated p38 mitogen-activated protein kinase (p38 MAPK) signaling, reduced nuclear translocation of the transcription factor EB (TFEB), and impaired autophagic flux, thereby promoting a pro-senescent cellular state. Metabolomic profiling revealed that PEX5 overexpression enhanced taurine biosynthesis by facilitating the peroxisomal localization of its key synthetic enzymes. Remarkably, exogenous taurine supplementation restored PEX5 levels in senescent fibroblasts and aged mouse lungs, mitigating senescence phenotypes and establishing a PEX5-taurine-PEX5 positive feedback loop. Together, these findings delineate a novel peroxisome-centered regulatory mechanism that integrates p38 MAPK-TFEB signaling and taurine metabolism to control cellular senescence. This work provides new insights into the interplay between organelle function and aging and highlights potential targets for therapeutic intervention in age-related lung diseases.