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.
APA
Lin X, Wu C, et al. (2026). Targeting miR-4653-3p/SLC25A51/SIRT3 axis to induce synthetic lethality in ARID1A-deficient colorectal cancer via blockade of DNA repair.. Journal of translational medicine, 24(1). https://doi.org/10.1186/s12967-026-07760-8
MLA
Lin X, et al.. "Targeting miR-4653-3p/SLC25A51/SIRT3 axis to induce synthetic lethality in ARID1A-deficient colorectal cancer via blockade of DNA repair.." Journal of translational medicine, vol. 24, no. 1, 2026.
PMID
41639843
Abstract
[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.
[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.
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