Nonhistone Post-translational Modifications as Integrative Signaling Networks in Podocyte Injury and Glomerular...

Podocytes are key structural components of the glomerular filtration barrier and are essential for maintaining selective protein filtration. Podocyte dysfunction is closely associated with proteinuria and the progression of glomerulosclerosis, constituting the common pathological basis of various chronic kidney diseases such as diabetic nephropathy and focal segmental glomerulosclerosis. While histone post-translational modifications have been extensively studied in podocyte biology, recent attention has shifted toward the regulatory roles of nonhistone post-translational modifications. By modulating protein stability, activity, localization, and interactions, these modifications participate in core biological processes such as apoptosis, cytoskeletal remodeling, inflammatory signaling, and metabolic reprogramming. Nevertheless, the strength of evidence is not uniform across post-translational modification categories. While some mechanisms have been directly demonstrated in podocytes, others are inferred mainly from broader kidney injury models or from studies in non-podocyte cell types. Accordingly, not all reported post-translational modification changes should be interpreted as equally well-established causal drivers of podocyte injury. This review focuses on the molecular regulatory networks and pathophysiological significance of major nonhistone post-translational modifications, including acetylation, phosphorylation, methylation, lactylation, ubiquitination, and SUMOylation. We further propose a hypothesis-generating and integrative conceptual model of podocyte deterioration, linking initiating pathological stimuli to stress transduction and downstream effector decompensation that may culminate in structural collapse. Importantly, this proposed cascade is not intended to represent a universally validated linear sequence or a definitive disease mechanism. Rather, it provides an organizing framework to generate testable hypotheses. We further highlight the therapeutic promise of targeting nonhistone post-translational modification pathways while acknowledging the considerable translational challenges that remain. By synthesizing the mechanistic landscape of nonhistone post-translational modifications, this review provides an integrated framework for advancing our understanding of podocytopathy pathogenesis and fostering the development of precision-targeted therapies.