A small-molecule TNIK inhibitor targets fibrosis in preclinical and clinical models. Idiopathic pulmonary fibrosis (IPF) is a severe, progressive lung disease with high mortality. Despite extensive research, effective therapies remain elusive. This study identifies TRAF2- and NCK-interacting kinase (TNIK) as a potential anti-fibrotic target using a predictive artificial intelligence (AI) approach. A small-molecule TNIK inhibitor, INS018_055, was developed and tested in preclinical models, showing anti-fibrotic and anti-inflammatory effects. In a phase I clinical trial involving 78 healthy participants, INS018_055 demonstrated safety and tolerability, with comparable results in a separate Chinese phase I trial. The drug was developed using a generative AI-driven drug-discovery pipeline, which identified TNIK as a key target for fibrosis. TNIK inhibition reduced fibrosis in lung and kidney models, and the compound showed selective activity against TNIK. INS018_055 inhibited TGF-β-induced EMT and FMT, reducing α-SMA and fibronectin expression. In vivo studies in mouse models of lung fibrosis showed significant reduction in fibrotic area and improved lung function. The compound also reduced inflammation in the LPS-induced acute lung injury model. An aerosolized form of INS018_055 was effective in treating lung fibrosis in rats. In kidney fibrosis models, INS018_055 reduced fibrosis and collagen deposition. The compound was well-tolerated in clinical trials, with no significant adverse effects. These findings suggest that TNIK inhibition is a promising therapeutic strategy for fibrotic diseases.A small-molecule TNIK inhibitor targets fibrosis in preclinical and clinical models. Idiopathic pulmonary fibrosis (IPF) is a severe, progressive lung disease with high mortality. Despite extensive research, effective therapies remain elusive. This study identifies TRAF2- and NCK-interacting kinase (TNIK) as a potential anti-fibrotic target using a predictive artificial intelligence (AI) approach. A small-molecule TNIK inhibitor, INS018_055, was developed and tested in preclinical models, showing anti-fibrotic and anti-inflammatory effects. In a phase I clinical trial involving 78 healthy participants, INS018_055 demonstrated safety and tolerability, with comparable results in a separate Chinese phase I trial. The drug was developed using a generative AI-driven drug-discovery pipeline, which identified TNIK as a key target for fibrosis. TNIK inhibition reduced fibrosis in lung and kidney models, and the compound showed selective activity against TNIK. INS018_055 inhibited TGF-β-induced EMT and FMT, reducing α-SMA and fibronectin expression. In vivo studies in mouse models of lung fibrosis showed significant reduction in fibrotic area and improved lung function. The compound also reduced inflammation in the LPS-induced acute lung injury model. An aerosolized form of INS018_055 was effective in treating lung fibrosis in rats. In kidney fibrosis models, INS018_055 reduced fibrosis and collagen deposition. The compound was well-tolerated in clinical trials, with no significant adverse effects. These findings suggest that TNIK inhibition is a promising therapeutic strategy for fibrotic diseases.