Maladaptive tubular repair is a major contributor to fibrosis and chronic kidney disease (CKD), yet the molecular regulators of this process remain poorly understood. We report that the E3 ubiquitin ligases WWP1 and TRIM65 are novel regulators of tubular fibrosis. Both ligases were markedly induced in human and experimental CKD. WWP1 induction correlates with declining renal function in humans, highlighting the potential clinical relevance of WWP1. Profibrotic factor PAI-1 promotes a robust induction of WWP1 and TRIM65 in both primary human renal epithelial cells as well as cell line (HK-2). The silencing of WWP1 or TRIM65 significantly attenuated PAI-1-induced fibrotic signaling. Mechanistically, PAI-1 triggers a signaling cascade in which suppression of the regenerative BMP-7/SMAD5 pathway permits c-Myc induction, resulting in WWP1 and TRIM65 upregulation. The elevated expression of these ligases subsequently promotes epithelial dedifferentiation and fibrotic growth arrest. Restoration of BMP-7 or SMAD5 signaling disrupted this cascade and reduced fibrosis in renal tubular cells. Our study establishes a previously unrecognized PAI-1–c-Myc–WWP1/TRIM65 axis governing tubular maladaptive repair and positions WWP1 as a potentially new therapeutic target for slowing CKD progression.