S100A4 Orchestrates Fibroblast Fate to Drive Fibrotic Remodeling

Fibroblast survival and dysregulated activation drive fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). During physiological wound repair, fibroblasts are transiently activated to restore tissue integrity and are subsequently cleared by programmed cell death. In fibrotic disease, however, fibroblasts evade apoptosis and persist in a pathologically activated state. Although S100A4 has been implicated in fibrotic lung disease, the mechanisms by which S100A4 governs fibroblast fate and sustains profibrotic behavior remain unclear. Here, we identify S100A4 as a key regulator of apoptosis-resistant, profibrotically activated fibroblasts through engagement of extracellular signal-regulated kinase (ERK) signaling. In primary murine lung fibroblasts, S100A4 activates ERK, resulting in a coordinated program of fibroblast activation, including increased migration, extracellular matrix (ECM) contractility, stress fiber formation, and alpha-smooth muscle actin (α-SMA) induction. Functionally, S100A4 confers resistance to apoptosis induced by pro-apoptotic and oxidative stress stimuli, as evidenced by reduced cleaved caspase-3 and preserved cell viability. Pharmacological blockade of ERK signaling attenuates these responses, supporting ERK as an important downstream mediator of S100A4-driven fibroblast activation and survival programs. Extending these findings to disease-relevant contexts, bleomycin (BLM)-induced lung injury in mice induces robust fibrotic remodeling, excessive collagen deposition, and transcriptional upregulation of S100A4. Consistently, primary lung fibroblasts from IPF patients exhibit elevated S100A4 expression, enhanced ERK activation, and increased α-SMA expression, demonstrating conservation of this signaling axis across experimental models and human disease. Importantly, siRNA-mediated knockdown of S100A4 in IPF fibroblasts suppresses ERK activation and attenuates expression of key profibrotic genes, indicating that S100A4 contributes to maintaining the fibrotic program in IPF fibroblasts. Collectively, these findings define a mechanistic link between S100A4-mediated fibroblast survival and activation that drives pathological matrix remodeling and identify S100A4 and ERK as potential therapeutic targets in pulmonary fibrosis.