Candidate microRNA networks in cyclophosphamide-associated ovarian injury and premature ovarian insufficiency: a structured narrative review

Premature ovarian insufficiency (POI) is characterized by loss of ovarian function before age 40, leading to infertility, hypoestrogenism, and long-term morbidity. Cyclophosphamide (CYC), an alkylating agent widely used in oncology and autoimmune diseases, is among the most gonadotoxic drugs. Beyond direct cytotoxicity, emerging evidence suggests that microRNAs (miRNAs) may modulate oxidative stress, apoptosis, autophagy, and inter-individual susceptibility to follicular loss after CYC exposure. We conducted a structured narrative review of PubMed, Scopus, and Web of Science records from 2015 to 2024, with targeted inclusion of relevant recent studies. We included in vitro, animal, and human evidence evaluating miRNA expression, regulation, or function in ovarian tissue, granulosa cells, circulating samples, or extracellular vesicles after CYC/chemotherapy-associated ovarian injury. Extracted variables included experimental model, exposure protocol, miRNA profile, targets, pathways, and functional outcomes. Review structure and critical appraisal were guided by SANRA. CYC-induced ovarian injury involves oxidative stress, DNA damage, granulosa-cell apoptosis, impaired autophagy, stromal-vascular remodeling, and follicular depletion. Direct CYC-related evidence supports miR-15b and miR-122-5p as pro-injury mediators, while let-7a and miR-22-3p appear protective or restorable in specific experimental models. miR-10a, miR-21, and miR-144-5p are supported mainly as therapeutic or exosome-delivered protective cargos in preclinical chemotherapy-associated ovarian injury models. Other miRNAs, including miR-23a/27a, miR-146a/146b-5p, miR-483-5p, and miR-15a, provide contextual evidence from POI, granulosa-cell apoptosis, oxidative-stress, cisplatin, or non-CYC ovarian injury models. These miRNAs converge on α-Klotho/TGF-β-SMAD, PI3K/Akt, Wnt/β-catenin, NF-κβ, CMKLR1, STAT1, and PTEN-related pathways. Human evidence remains limited, mostly observational, and not CYC-specific. miRNAs are plausible epigenetic mediators of CYC-associated ovarian injury, but current data support a candidate regulatory network rather than a validated diagnostic, prognostic, or therapeutic signature. Circulating miRNAs remain exploratory biomarkers, and miRNA-targeted or exosome-based interventions require validation in human-relevant models before clinical translation. These molecular insights may inform future risk stratification, mechanistic monitoring, and post-treatment reproductive care in women exposed to alkylating agents.