Lysine malonylation (Kmal) is a novel post-translational modification (PTM) implicated in numerous biological processes. Our recent study finds that human sperm proteins are modified by Kmal, but the functional significance of Kmal in human sperm remains unclear. The present study shows that Kmal primarily occurs in human sperm tail proteins with molecular weights ranging from 15 to 250 kDa. Similar to somatic cells, Kmal is derived from malonyl-CoA, with acyltransferase P300 and sirtuin 5 (SIRT5) potentially acting as the writer and eraser, respectively, for Kmal in human sperm. The Kmal level in asthenozoospermic sperm is significantly higher than that in normozoospermic sperm and exhibits a negative correlation with progressive motility. Elevated Kmal levels in asthenozoospermic sperm are associated with reduced sperm SIRT5 and ATP levels, as well as inhibited glycolysis. Furthermore, the induction of sperm Kmal by sodium malonate significantly diminishes the motility and penetration ability of normozoospermic samples by reducing sperm [Ca²⁺]i, ATP, and cAMP levels, and by suppressing glycolysis and PKA activity. Our findings elucidate the regulatory function of Kmal in human sperm motility and its association with asthenozoospermia, thereby offering insights for the diagnosis and treatment of idiopathic male infertility.

Male infertility has emerged as a significant global concern, with male factors accounting for approximately 30% to 50% of infertility cases. Oxidative stress is recognized as the primary pathological mechanism affecting sperm structure and function. The development and application of chemically synthesized drug therapies are limited by lengthy research and development processes and significant adverse effects. Conversely, Traditional Chinese Medicine (TCM) compounds offer promising clinical applications for enhancing male reproductive function, attributed to their distinctive advantages of multi-target coordination and holistic regulation. This paper systematically reviews classical TCM compounds, such as those that tonify the kidney and benefit essence, warm and invigorate kidney Yang, and replenish Qi and nourish blood. It also examines the molecular mechanisms of active natural ingredients, including flavonoids, polyphenols, terpenes, alkaloids, and polysaccharides. These compounds improve male fertility by modulating oxidative stress-related signaling pathways. Furthermore, this review anticipates future research trajectories and potential applications within this domain, with the objective of establishing a theoretical basis for the clinical treatment of idiopathic male infertility and the development of novel pharmacological interventions.

The global incidence of male infertility is increasing annually, with environmental pollution identified as a significant contributing factor. Nonylphenol (NP), an emerging environmental pollutant characterized by high biological toxicity and limited biodegradability, has effects on male fertility and its underlying mechanisms that remain inadequately understood. This study conducted a systematic search of various databases, identifying 68 protein targets closely associated with NP and asthenozoospermia. GO and KEGG pathway enrichment analyses reveal that NP may impair human sperm function by disrupting endocrine resistance, prolactin signaling pathways, and hormone signaling pathways. Utilizing the STRING platform and Cytoscape software, the study further identified 10 core target proteins. The top three affinity scores for NP with protein targets, ranked from highest to lowest, were STAT3, ESR1, and ESR2. This study conducted a comprehensive investigation into the effects of varying concentrations of NP (1, 10, 100 nM) on human sperm motility and its underlying mechanisms through in vitro experiments. NP inhibits the motility of uncapacitated sperm and impairs the ability of capacitated sperm to penetrate viscous media, with the inhibitory effects being positively correlated with NP concentration. Further mechanistic analyses demonstrated that NP exposure leads to the downregulation of ESR1, Nrf2, SRC protein levels in sperm, and an increase in STAT3 phosphorylation, elevated intracellular ROS levels, and depolarization of the mitochondrial membrane potential. These results suggest that NP may exert its effects via the ESR1, STAT3, Nrf2 and SRC signaling pathways, inducing oxidative stress in sperm and ultimately impairing human sperm motility.