Proteomic Landscape of Spermatozoa Under Inflammatory and Oxidative Injury: Molecular Mechanisms and Clinical Translation.

Abstract

Male infertility is a multifactorial condition in which conventional semen analysis provides limited insight into the molecular mechanisms underlying sperm dysfunction. Inflammatory and oxidative processes are major contributors to impaired male reproductive function, acting through interconnected alterations in redox homeostasis, immune activation, and protein integrity. Because mature spermatozoa have minimal transcriptional and translational capacity, oxidative and inflammatory damage to proteins may persist and substantially affect motility, capacitation, fertilization competence, and reproductive outcomes. This review examines how sperm proteomics can characterize the molecular landscape of inflammatory and oxidative injury in male infertility. Particular attention is given to pre-analytical variables, sperm purification, protein extraction, bottom-up LC-MS/MS workflows, data-dependent and data-independent acquisition, quantitative strategies, and targeted or orthogonal validation. Proteomic evidence identifies coordinated remodeling of flagellar and motility proteins, Ca²⁺-signaling networks, mitochondrial bioenergetics, antioxidant defenses, membrane-associated pathways, and proteins involved in sperm-oocyte interaction. These signatures may improve mechanistic patient stratification and support the development of biomarker panels linked to clinically relevant endpoints. Nevertheless, routine implementation remains limited by methodological heterogeneity, inadequate standardization, small study populations, and insufficient prospective validation. Integrating proteomic signatures with redox, inflammatory, clinical, and reproductive outcome data may facilitate the transition from descriptive semen assessment and empirical treatment toward mechanism-based precision andrology.