GREM1: Dual roles in cancer and fibrosis with emerging therapeutic opportunities

Cancer and fibroproliferative diseases, such as pulmonary and renal fibrosis, represent major global health challenges due to their progressive nature and the scarcity of effective therapeutic options. Gremlin 1 (GREM1), a member of the bone morphogenetic protein (BMP) antagonist family, has emerged as a central regulator of cellular and extracellular dynamics, exhibiting dual roles in oncogenesis and fibrosis. By modulating BMP and TGF-β signaling pathways, GREM1 orchestrates critical pathogenic processes, including immune evasion, stromal dynamics, fibroblast activation, and angiogenesis. This review compiles current mechanistic insights into GREM1's dual roles in cancer and fibrosis, highlighting its potential as both a biomarker and a therapeutic target. GREM1 contributes to tumor progression by promoting an immunosuppressive tumor microenvironment (TME) and therapy resistance while driving extracellular matrix deposition and tissue remodeling in fibrotic disorders. Emerging therapeutic strategies, including demethyleneberberine (DMB), anti-GREM1 antibodies, and circular RNAs, demonstrate potential in mitigating GREM1-driven pathological processes. GREM1's pivotal role in the pathophysiology of cancer and fibrosis highlights its promise as a target for innovative combination therapies and biomarker-based precision medicine approaches. However, translating these insights into clinical practice requires addressing challenges related to delivery specificity, off-target effects, and patient heterogeneity.