ROS-SUMO Crosstalk in Oxidative Stress: Disease Mechanisms and Reproductive Health.

Oxidative stress disrupts protein function through direct oxidation and triggers adaptive post-translational modifications. Among these, small ubiquitin-like modifier (SUMO)-ylation mediates fast and reversible remodeling of nuclear and cytoplasmic proteins. Redox regulation of the SUMO E1-E2 conjugation complex and specific SUMO proteases, such as SENP1 and SENP3, allows ROS to influence SUMO turnover and substrate selectivity. This defines SUMOylation as a versatile stress-response module under oxidative stress. In this review, we describe oxidative stress-induced remodeling of SUMO conjugation and deconjugation, with a focus on SUMO2/3 responses that transiently adjust transcription, DNA damage repair, and nuclear body dynamics. We discuss disease-relevant SUMO targets and pathological alterations in SUMO regulation across four major disease categories: neurodegenerative diseases, cardiovascular disease, cancer, and diabetes/metabolic diseases. In addition, we summarize emerging evidence connecting redox-sensitive SUMO remodeling to germ-cell function and reproductive health. Together, these perspectives highlight the dual role of SUMOylation as both a driver of stress adaptation and a tractable target for informing therapeutic strategies targeting the SUMO pathway.