Chronic lung diseases represent a significant global health burden, especially among aging populations [1]. Despite considerable advancements in understanding and managing these conditions, the fundamental mechanisms underlying lung aging remain largely undefined, and current therapeutic options exhibit limited clinical effectiveness [2]. As aging constitutes the primary risk factor for chronic lung diseases, there has been growing interest in exploring the role of cellular senescence to better understand disease pathogenesis and to identify novel therapeutic targets [3]. Cellular senescence, characterized by irreversible cell cycle arrest and distinct alterations in cellular morphology and physiology, is triggered by various stressors [[4], [5], [6]]. Accumulation of senescent cells contributes significantly to tissue aging and dysfunction, whereas their selective clearance via senolytic agents has shown potential in restoring tissue function and extending healthy lifespan [7,8]. Accumulating evidence indicates that impaired organelle functions and disrupted inter-organelle communication significantly contribute to cellular senescence, thereby promoting multiple aging-related pathologies [9,10].

Peroxisomes are essential membrane-bound organelles found in nearly all eukaryotic cells, playing critical roles in diverse metabolic processes, including the β-oxidation of very long-chain fatty acids, α-oxidation of branched-chain and 2-hydroxy fatty acids, synthesis of plasmalogens and bile acids, and metabolism of reactive oxygen species (ROS) [11]. The peroxin (PEX) protein family orchestrates peroxisome biogenesis and the import of matrix proteins, primarily through the shuttle receptor PEX5, which recognizes peroxisomal targeting signals (PTS1) on target proteins in the cytosol [12,13]. Mutations in PEX5 cause Zellweger spectrum disorders (ZSDs), severe conditions marked by dysfunctional peroxisomes that typically lead to early death [11]. Animal models deficient in PEX5 similarly display significantly shortened lifespans [[14], [15], [16], [17]]. Moreover, age-dependent reductions in PEX5 and associated peroxisomal dysfunctions have been observed in model organisms, including C. elegans and mouse cortical neurons, underscoring potential links between PEX5 and aging processes [18,19]. Notably, dysfunctional peroxisomes with impaired PTS1-protein import accumulate in aged human fibroblasts [20]. However, direct evidence linking peroxisomal dysfunction and PEX5 deficiency to cellular senescence remains limited, especially in the context of human chronic lung diseases.

Beyond its canonical role in peroxisomal protein import, PEX5 is increasingly recognized as a critical regulator of autophagy. Interaction of PEX5 with tuberous sclerosis complex 2 (TSC2) can suppress mammalian target of rapamycin complex 1 (mTORC1) activity and promote autophagy in response to peroxisomal ROS [21]. Additionally, ROS-induced phosphorylation of PEX5 by ataxia-telangiectasia mutated (ATM) kinase leads to its ubiquitylation and recruitment of the autophagy adapter p62, stimulating selective degradation of peroxisomes (pexophagy) [22]. Conversely, depletion of PEX5 disrupts autophagic processes by modulating mTOR signaling and inhibiting nuclear translocation of transcription factor EB (TFEB) under nutrient deprivation conditions [23]. Recent studies further highlight the significance of PEX5 in maintaining autophagic flux, spermatogenesis, and cellular homeostasis under stress conditions [16,24]. Nevertheless, the precise molecular mechanisms by which PEX5 regulates autophagy and its potential link to cellular senescence remain incompletely understood.

In this study, we examined the regulation of PEX5 during replicative and oxidative stress-induced senescence in human primary fetal lung fibroblasts (HFL-1) and identified PEX5 deficiency as a critical factor promoting premature cellular senescence. Mechanistically, we demonstrate that PEX5 attenuates senescence by facilitating TFEB nuclear translocation through suppression of p38 MAPK signaling pathway and augmentation of taurine biosynthesis. Our findings uncover a novel mechanistic axis involving PEX5-mediated integration of retrograde signaling and metabolic pathways in cellular senescence, providing new insights into the pathophysiology and potential therapeutic targets for chronic lung diseases associated with aging.