<p>Breast cancer remains a major global health challenge for women. Chemotherapy resistance is a key driver of breast cancer recurrence and metastasis. Although meiotic nuclear division 1 (MND1) has been characterized as an oncogenic factor involved in mitotic progression and homologous recombination (HR), the precise molecular mechanisms underlying these MND1-mediated processes remain unclear. The expression of MND1 in breast cancer cell lines was evaluated by RT-qPCR and western blot. The functional effects of MND1 were assessed through a series of in vitro and in vivo assays, including cell proliferation assays, determination of resistance curves, DNA damage detection and flow cytometry. Protein interactions among MND1, RAD51, and USP5 were determined by co-immunoprecipitation assays. Transcriptional regulation of MND1 by E2F1 and promoter methylation status were analyzed using luciferase reporter assays and bisulfite sequencing PCR, respectively. We demonstrated that MND1 is upregulated in breast cancer and associated with cancer progression and cisplatin resistance. Mechanistically, MND1 promotes HR repair by recruiting USP5 to deubiquitinate and stabilize RAD51. Furthermore, E2F1 induces promoter hypomethylation and transcriptionally activates MND1 by binding to its promoter. Our findings establish a role for MND1 in regulating chemosensitivity and provide new insights into relevant gene interaction networks. The identified E2F1/MND1/USP5/RAD51 feedback loop underscores the potential of MND1 as a therapeutic target for breast cancer.</p>