Targeting miR-4653-3p/SLC25A51/SIRT3 axis to induce synthetic lethality in ARID1A-deficient colorectal cancer via blockade of DNA repair.

BACKGROUND: ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, functions as a tumor suppressor and is frequently inactivated across various cancer types. Consequently, ARID1A deficiency has emerged as a promising therapeutic target. METHODS: In this study, we conducted a high-throughput screening of a microRNA (miRNA) mimic library using ARID1A isogenic colorectal cancer (CRC) cell lines and identified a synthetic lethal interaction between ARID1A and miR-4653-3p. RESULTS: MiR-4653-3p selectively inhibited the proliferation of ARID1A-deficient CRC cells. Mechanistically, miR-4653-3p directly targets SLC25A51, a mitochondrial NAD⁺ transporter gene, leading to impaired SIRT3 enzymatic activity. Since both ARID1A and SIRT3 play critical roles in DNA damage repair, their concurrent loss exacerbates DNA damage accumulation and promotes apoptosis. CONCLUSIONS: In conclusion, our findings reveal a novel synthetic lethality between ARID1A and miR-4653-3p, and suggest that targeting the miR-4653-3p/SLC25A51/SIRT3 axis, in combination with agents that disrupt DNA damage response, may offer a promising therapeutic strategy for ARID1A-deficient CRC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-026-07760-8.