Intrinsic Inflammatory Signaling in Life and Death of Podocytes

Podocytes are terminally differentiated components of the glomerular filtration barrier whose structural integrity depends on coordinated signaling between the slit diaphragm, actin cytoskeleton, mitochondria, and stress-response machinery. Evidence from cultured podocytes, experimental kidney disease, human tissue, and selected podocyte-specific genetic models indicates that podocytes can initiate cell-autonomous inflammatory responses rather than functioning solely as passive targets of systemic inflammation. This review examines how NF-κB, p38 MAPK, JAK–STAT, cGAS–STING, NLRP3 inflammasome, and Rho-family GTPase signaling interact with cytoskeletal remodeling, mitochondrial dysfunction, senescence, regulated cell death, and podocyte detachment. Particular attention is given to the distinction between podocyte-specific evidence and findings obtained from whole-kidney analyses, global genetic models, or pharmacological interventions. The available evidence supports a context-dependent network in which inflammatory signaling may initially contribute to adaptation but, when sustained, promotes barrier dysfunction and irreversible podocyte loss. We also assess therapeutic strategies targeting inflammatory sensors, kinases, inflammasome components, cytoskeletal regulators, and metabolic stress pathways. Most remain preclinical, emphasizing the need for podocyte-targeted delivery, rigorous cell-specific validation, and human translational studies.