Antifibrotics with Cross-Indication Potential: Challenges and Progress Towards a Universal Fibrosis-Modifying Therapy

Abstract: Organ fibrosis is a chronic, progressive condition that frequently results in organ dysfunction and failure. Despite its high morbidity and mortality, substantial therapeutic gaps persist for fibrosis across all organ systems. The compartmentalization of fibrosis research by organ system has impeded the development of antifibrotic therapies with cross-organ applicability. However, the shared pathobiology of fibrosis involves convergent signaling through the TGF-β/SMAD axis, receptor tyrosine kinase-mediated fibroblast activation, Wnt/β-catenin-driven myofibroblast differentiation, and amplification of oxidative stress. These conserved mechanisms support the emerging concept of fibrotic endotypes and justify the pursuit of cross-indication antifibrotic drug development, specifically for fibrotic processes in lung, liver, kidney and heart. This review examines the cross-indication potential of currently approved antifibrotics (nintedanib, pirfenidone, nerandomilast) and emerging agents by evaluating their mechanisms of action, preclinical and clinical evidence, translational potential in non-pulmonary fibrosis, and insights from recent clinical trials. Recent data from Phase 3 trials underscore the necessity of multi-target rather than single-target strategies. Key barriers to universal antifibrotic therapy, such as target redundancy, gaps in preclinical-to-clinical translation, biological heterogeneity, and suboptimal trial design, are also discussed. We propose that an endotype guided, precision-medicine strategy using multi-omics profiling and cross-organ adaptive trial designs may help bridge this gap and remains the most promising path toward a universal fibrosis-modifying therapy. Keywords: tissue fibrosis, therapy, pathogenesis, antifibrotic, lung, liver, kidney, heart