ETHNOPHARMACOLOGICAL RELEVANCE: Oligoasthenozoospermia (OAS) is among the leading causes of male infertility and is characterized by a complex pathogenesis. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a central transcription factor by which cellular redox homeostasis is maintained, chiefly through the Keap1-Nrf2-antioxidant response element (ARE) signaling pathway. Emerging evidence indicates that Traditional Chinese Medicine (TCM) has therapeutic potential to modulate Nrf2-related mechanisms and thereby ameliorate OAS.
AIM OF THE STUDY: This review is intended to summarize the role of the Nrf2 pathway in OAS pathogenesis and to evaluate therapeutic advances in TCM interventions, with emphasis on mechanistic features and potential applications in OAS management.
MATERIALS AND METHODS: Relevant literature was systematically retrieved from PubMed, Web of Science, EMBASE, the Cochrane Library, Wanfang, and the China National Knowledge Infrastructure (CNKI). The following keywords were used: "oligoasthenozoospermia," "Nrf2," "oxidative stress," "ferroptosis," "traditional Chinese medicine," "Chinese herbal medicine," and "herbal compounds." Both experimental and clinical studies were included to comprehensively evaluate TCM-mediated regulation of Nrf2 in OAS. Inclusion criteria were as follows: ① In vivo and in vitro studies relevant to the topic, as well as systematic reviews and meta-analyses. ② Articles published in the past 10 years in peer-reviewed journals, in Chinese or English. ③ Studies evaluating Chinese medicine interventions-including classical formulae, single herbs, extracts, purified active constituents, and modern preparations-and acupuncture for OAS or related phenotypes. ④ Evidence implicating the Nrf2/Keap1/ARE axis and its upstream or downstream nodes. ⑤ Reporting at least one quantitative outcome with sufficient statistics; experimental studies were required to specify the disease or injury model and dosing, route, and regimen. Exclusion criteria were as follows: ① Abstracts, conference papers, theses/dissertations, editorials/opinions, preprints, and non-systematic narrative reviews. ② Absence of a control group or missing key dosing/model details; missing primary outcomes or statistical results that precluded effect estimation. ③ Not related to OAS or lacking involvement of the Nrf2-related pathway; studies confined to nonreproductive models that could not be extrapolated to OAS. ④ Overlapping datasets; only the most complete or the most recent report was retained.
RESULTS: Activation of Nrf2 is associated with scavenging of reactive oxygen species, suppression of lipid peroxidation and ferroptosis, stabilization of mitochondrial function, mitigation of apoptosis and endoplasmic reticulum stress, repair of the blood-testis barrier, and preservation of testicular microenvironmental homeostasis. In this review, approximately 25 active compounds, 6 single-herb interventions, 20 multi-herb formulas, and several acupuncture modalities were identified; collectively, these TCM approaches target Nrf2-related pathways-modulating oxidative stress, ferroptosis, inflammation, and apoptosis-to promote spermatogenesis and improve reproductive function. Accumulating preclinical and clinical evidence indicates that TCM formulas and their active constituents protect against testicular injury and improve semen quality, thereby providing mechanistic underpinnings and practical strategies for OAS treatment.
CONCLUSIONS: The Nrf2 signaling pathway is central to OAS pathogenesis through the regulation of oxidative stress, ferroptosis, autophagy, apoptosis, and endocrine homeostasis. TCM interventions, characterized by multi-component and multi-target actions, show promise and provide mechanistic insights and theoretical support for OAS prevention, treatment, and clinical translation. Integration of mechanistic research with clinical validation may facilitate precise targeting of Nrf2 and advance TCM modernization, thereby offering potentially safer and more effective therapeutic strategies for patients with OAS.
