OC-STAMP deficiency limits MMT and ameliorates silicosis by inhibiting macrophage phenotype differentiation

Silicosis is a progressive fibrotic lung disease characterized by myofibroblast accumulation and excessive extracellular matrix deposition, for which effective therapeutic interventions remain limited. Macrophage to myofibroblast transition (MMT) has emerged as a critical cellular source of myofibroblasts during silicosis, yet the molecular regulators governing this process are not fully understood. Osteoclast stimulatory transmembrane protein (OC-STAMP) is a multi-transmembrane protein originally identified in osteoclast differentiation, but its role in silicosis remains unexplored. In this study, we investigated the expression and functional involvement of OC-STAMP in silicosis using in vivo and in vitro models. We found that OC-STAMP was significantly upregulated in the lung tissues of silicotic mice and MH-S stimulated by SiO₂, and was predominantly localized to macrophages. Macrophage-specific conditional knockout of Ocstamp (Ocstamp^{flox/flox; Lyz2-cre}) markedly suppressed M2 macrophage polarization and MMT, and attenuated the progress of silicosis. Mechanistically, Ocstamp knockdown attenuated JAK1/STAT6 signaling, whereas Ocstamp overexpression enhanced it, and pharmacological inhibition of JAK1 with Upadacitinib reversed OC-STAMP-induced MMT and signaling activation. Collectively, these findings identify OC-STAMP as a previously unrecognized regulator of MMT via JAK1/STAT6 signaling, highlighting OC-STAMP as a potential therapeutic target for silicosis and other fibrotic diseases.