IER3-N-cadherin axis contributes to apoptosis resistance in dermal fibroblasts under profibrotic conditions

Abstract

Background: Persistent activation and resistance to apoptosis of dermal fibroblasts contribute to pathological skin fibrosis. Immediate early response 3 (IER3) is a stress-responsive protein involved in cell survival, but its role in cutaneous fibrosis remains unclear. We investigated the functional significance of IER3 in dermal fibroblasts and its potential contribution to fibrosis. Methods: IER3 expression was examined in skin samples from patients with systemic sclerosis, keloids, and hypertrophic scars. Primary human dermal fibroblasts were stimulated with transforming growth factor-{beta}1 (TGF-{beta}1). RNA sequencing, siRNA-mediated gene silencing, quantitative PCR, and flow cytometric apoptosis assays were performed to investigate the downstream mechanisms and functional consequences of IER3 expression. Results: IER3 expression was increased in dermal fibroblasts within fibrotic skin lesions and was induced by TGF-{beta}1 independently of SMAD3 and MEK/ERK signaling. Transcriptomic analysis identified CDH2, encoding N-cadherin, as a downstream target of IER3. Moreover, TGF-{beta}1 induced CDH2 expression in a SMAD3 phosphorylation-dependent manner. IER3 knockdown attenuated TGF-{beta}1-induced CDH2 expression, whereas CDH2 knockdown did not affect IER3 expression. Furthermore, CDH2 knockdown enhanced staurosporine-induced apoptosis in TGF-{beta}1-stimulated fibroblasts, accompanied by a shift in apoptosis-related gene expression toward a pro-apoptotic profile. Conclusion: Our findings identify a previously unrecognized IER3-N-cadherin regulatory axis that may promote dermal fibroblast survival by suppressing apoptosis under profibrotic conditions. Targeting this pathway may represent a novel therapeutic strategy for persistent skin fibrosis.