Small molecules targeting regulated cell death for chronic kidney disease therapy

Chronic kidney disease (CKD) is a significant contributor to the global morbidity of non-communicable diseases and is predicted to become the fifth leading cause of death worldwide. However, effective treatments that directly target the underlying causes of CKD remain limited due to its complicated pathogenesis. Recent research has increasingly focused on elucidating the molecular mechanisms and identifying new therapeutic targets of CKD. In recent years, regulated cell death (RCD) has been highlighted as a central mechanism in the development and progression of CKD, suggesting that targeting specific RCD signaling pathways may offer effective strategies for CKD. Emerging research reveals that small molecules can effectively target different types of RCD in the context of CKD, including apoptosis, autophagy-dependent cell death, pyroptosis, ferroptosis and necroptosis. In this review, we summarize current understanding of the mechanism of RCD in CKD. Importantly, we emphasize the regulatory mechanism of small molecules on disturbed RCD to alleviate CKD. Taken together, this review enhances the comprehension of small molecules as modulators of RCD against CKD, which will provide new insights and potential avenues for CKD therapy. • Various regulated cell death (RCD) pathways, including apoptosis, autophagy-dependent cell death, pyroptosis, ferroptosis, and necroptosis, contribute to renal dysfunction in chronic kidney disease (CKD). • Small-molecule therapeutics targeting RCD pathways have shown potential in reducing kidney injury and inhibiting fibrotic signaling. • Clinical and translational research highlights RCD-targeted strategies as a promising approach to overcoming therapeutic limitations and advancing safer treatment options for CKD.