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Introduction Dysregulated fibroblast activation lies at the core of scleroderma pathogenesis, driving persistent inflammation, excessive collagen secretion, and progressive fibrosis in the skin and, at advanced stages, internal organs. Despite growing insights into the cellular complexity of the disease, the upstream molecular mediators that influence fibroblast heterogeneity and dictate subtype-specific fibroblast responses remain inadequately defined. Identifying such key mediators is essential, not only for elucidating mechanisms of fibrogenesis but also for uncovering actionable therapeutic targets in a disease that remains effectively untreatable. Here, leveraging a novel mouse model of systemic sclerosis (SSc), we identify the matricellular protein Mindin (Spondin-2) as a pivotal driver of subtype-specific profibrotic fibroblast responses contributing to dermal fibrosis in scleroderma.Material and Methods We utilised a novel mouse model of systemic sclerosis (Rana et al., JID, 2023) that recapitulates key clinical features of the human disease, including Raynaud’s phenomenon. For in vitro studies, primary dermal fibroblasts were isolated from neonatal mice to purify the Papillary and reticular fibroblast subpopulations by fluorescence-activated cell sorting (FACS) using CD26 and Sca1 as markers. Gene and protein expression were analysed by qRT-PCR and immunostaining, while migratory and contractile activities of fibroblasts were assessed using Boyden chamber and collagen gel contraction assays. Bulk and single-cell RNA sequencing are performed to identify molecular drivers, key signalling pathways, and fibroblast responses across different stages of the disease progression.Results We observed that Mindin is upregulated in the skin of scleroderma patients. Both in vivo (SSc mouse model) and in vitro (cultured fibroblast subtypes) studies demonstrated that Mindin is sufficient to activate distinct dermal fibroblast subpopulations. Specifically, Mindin promotes inflammatory cytokine production and migration in the reticular fibroblast subpopulation, while papillary fibroblasts respond with enhanced contractility and collagen secretion. Genetic ablation of Mindin in the SSc mouse model significantly reversed the disease phenotype, establishing Mindin and its signalling axis as indispensable drivers of fibrosis. Mechanistically, the N-terminal domain of Mindin alone recapitulated the profibrotic effects of the full-length protein, enabling identification of its cognate receptor(s) via co-immunoprecipitation. Through an integrated computational and experimental approach, we identified specific pattern recognition receptors, which, in coordination with Src-family kinases, Rho GTPases, and the NF-kB pathway, orchestrate distinct subtype-specific fibroblast responses under Mindin.Conclusions Our findings position Mindin as a pivotal upstream regulator of fibroblast heterogeneity and a critical driver of fibrosis in scleroderma, offering a new therapeutic target for this currently untreatable disease.