Repurposing the Antidepressant Sertraline: A Systematic Scoping Review of Its Anticancer Mechanisms

Drug repurposing offers a cost-effective and time-efficient strategy for identifying new cancer therapies. Sertraline, a widely prescribed selective serotonin reuptake inhibitor (SSRI), has shown promising anticancer properties through modulation of key pathways involved in tumor survival, stress adaptation, and therapeutic resistance. This scoping review systematically evaluates the current evidence on sertraline's anticancer mechanisms, efficacy, and translational potential. A systematic search of PubMed, EMBASE, Scopus, and Web of Science was conducted in accordance with PRISMA-ScR guidelines. Eligible studies included in vitro, in vivo, and clinical investigations. Data on cancer types, mechanisms, assays, and outcomes were extracted and synthesized. Of 97 screened articles, 67 met inclusion criteria, comprising 56 preclinical studies, nine population-based studies, and two mixed-methods reports. Sertraline induces apoptosis via mitochondrial dysfunction, caspase activation, and Bcl-2 downregulation, disrupts autophagy and the unfolded protein response, and impairs serine/glycine metabolism through SHMT inhibition. It also suppresses oncogenic signaling via mTOR and TCTP modulation. In vivo studies confirmed tumor growth inhibition in various cancer models, including breast, lung, glioblastoma, and liver. Sertraline enhances the efficacy of chemotherapy, radiotherapy, and targeted therapies by sensitizing resistant cells, modulating immune responses, and impairing metabolic recovery. Retrospective studies suggest no increased cancer risk with SSRI use and hint at protective associations in select malignancies. While current evidence is predominantly preclinical, sertraline's multi-targeted action and established safety profile support its candidacy for repurposing. Further translational research and biomarker-driven clinical trials are warranted to validate its therapeutic niche and optimize its integration into oncology.