{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T16:38:03Z","timestamp":1789663083167,"version":"4.0.1"},"reference-count":29,"publisher":"IMR Press","issue":"7","license":[{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005046","name":"Heilongjiang Provincial Natural Science Foundation of China","doi-asserted-by":"crossref","award":["LH2024H082"],"award-info":[{"award-number":["LH2024H082"]}],"id":[{"id":"10.13039\/501100005046","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Qiqihar Medical Institute Foundation","award":["QMSI2024M-10"],"award-info":[{"award-number":["QMSI2024M-10"]}]},{"name":"Qiqihar Medical Institute Foundation","award":["2025-ZDPY-002"],"award-info":[{"award-number":["2025-ZDPY-002"]}]},{"DOI":"10.13039\/501100003851","name":"Education Department Foundation of Heilongjiang Province","doi-asserted-by":"crossref","award":["2024-KYYWF-0339"],"award-info":[{"award-number":["2024-KYYWF-0339"]}],"id":[{"id":"10.13039\/501100003851","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Construction Project of Dominant Characteristic Disciplines of Qiqihar Medical University","award":["QYZDXK-003"],"award-info":[{"award-number":["QYZDXK-003"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background:Poly(ADP-ribose) polymerase inhibitors (PARPi) have shown limited efficacy in gastric cancer, primarily due to the rarity of inherent homologous recombination (HR) deficiency. The nuclear Arp2\/3 complex was recently implicated in DNA double-strand break repair via HR. Here, we investigate whether pharmacological inhibition of Arp2\/3 can induce a functional HR-deficient state to synergize with PARPi in gastric cancer cells.Methods:HR repair efficiency was assessed using a direct repeat green fluorescent protein (DR-GFP) reporter assay in HEK-293T cells following Arp2\/3 inhibition with CK666, siRNA-mediated knockdown, or CRISPR\/Cas9-mediated knockout of ACTR2\/ACTR3. HGC-27 and AGS gastric cancer cells were treated with CK666 alone and in combination with olaparib or niraparib. Cell viability and synergy were evaluated by Cell Counting Kit-8 (CCK-8) and clonogenic assays (n = 3 independent experiments). DNA damage and apoptosis were assessed by immunofluorescence for gamma H2A histone family member X (\u03b3H2AX) foci (\u2265100 cells per condition) and Western blot analysis for cleaved PARP.Results:Arp2\/3 inhibition with CK666 significantly impaired HR repair efficiency in the DR-GFP assay (p &lt; 0.01). This effect was recapitulated by genetic knockdown or knockout of ACTR2\/ACTR3. CK666 alone exerted minimal cytotoxicity, but synergized with both olaparib and niraparib to suppress proliferation (Combination Index &lt;1), reducing the half-maximal inhibitory concentration (IC50) of PARPi by approximately threefold. Combination treatment markedly enhanced \u03b3H2AX foci formation (p &lt; 0.0001) and increased the level of cleaved PARP compared with either monotherapy.Conclusions:Inhibition of Arp2\/3 compromises HR repair capacity, thereby creating a synthetic lethal interaction with PARP inhibition in gastric cancer cells. This combination strategy represents a promising therapeutic approach to broaden the clinical utility of PARPi in HR-proficient tumors and may also enable dose reduction to mitigate associated toxicities.<\/jats:p>","DOI":"10.31083\/fbl51619","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:17:49Z","timestamp":1785413869000},"source":"Crossref","is-referenced-by-count":1,"title":["Arp2\/3 Inhibition Synergizes With PARP Inhibitors by Impairing Homologous Recombination in Gastric Cancer Cells"],"prefix":"10.31083","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-4000-778X","authenticated-orcid":true,"given":"Wenlong","family":"Li","sequence":"first","affiliation":[{"name":"Laboratory of Protein Structure and Function, Institute of Medicine and Pharmacy, Qiqihar Medical University, 161006 Qiqihar, Heilongjiang, China"},{"name":"School of Medical Technology, Qiqihar Medical University, 161006 Qiqihar, Heilongjiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7700-7599","authenticated-orcid":true,"given":"Xinyue","family":"Pei","sequence":"additional","affiliation":[{"name":"Laboratory of Protein Structure and Function, Institute of Medicine and Pharmacy, Qiqihar Medical University, 161006 Qiqihar, Heilongjiang, China"},{"name":"School of Basic Medical Sciences, Qiqihar Medical University, 161006 Qiqihar, Heilongjiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1039-6960","authenticated-orcid":true,"given":"Yongpei","family":"Li","sequence":"additional","affiliation":[{"name":"Laboratory of Protein Structure and Function, Institute of Medicine and Pharmacy, Qiqihar Medical University, 161006 Qiqihar, Heilongjiang, China"},{"name":"School of Basic Medical Sciences, Qiqihar Medical University, 161006 Qiqihar, Heilongjiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanji","family":"Lu","sequence":"additional","affiliation":[{"name":"Laboratory of Protein Structure and Function, Institute of Medicine and Pharmacy, Qiqihar Medical University, 161006 Qiqihar, Heilongjiang, China"},{"name":"School of Medical Technology, Qiqihar Medical University, 161006 Qiqihar, Heilongjiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5975-6572","authenticated-orcid":true,"given":"Xian","family":"Hong","sequence":"additional","affiliation":[{"name":"Laboratory of Protein Structure and Function, Institute of Medicine and Pharmacy, Qiqihar Medical University, 161006 Qiqihar, Heilongjiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8173-2346","authenticated-orcid":true,"given":"Ming","family":"Sui","sequence":"additional","affiliation":[{"name":"Laboratory of Protein Structure and Function, Institute of Medicine and Pharmacy, Qiqihar Medical University, 161006 Qiqihar, Heilongjiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0970-7115","authenticated-orcid":true,"given":"Qiang","family":"Li","sequence":"additional","affiliation":[{"name":"Laboratory of Protein Structure and Function, Institute of Medicine and Pharmacy, Qiqihar Medical University, 161006 Qiqihar, Heilongjiang, China"},{"name":"School of Medical Technology, Qiqihar Medical University, 161006 Qiqihar, Heilongjiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0806-7045","authenticated-orcid":true,"given":"Xueying","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Hospital of Qiqihar, 161005 Qiqihar, Heilongjiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5560-5527","authenticated-orcid":true,"given":"Jingqiu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Hospital of Qiqihar, 161005 Qiqihar, Heilongjiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2708-8321","authenticated-orcid":true,"given":"Enming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Hospital of Qiqihar, 161005 Qiqihar, Heilongjiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6361-1114","authenticated-orcid":true,"given":"Yihan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Hospital of Qiqihar, 161005 Qiqihar, Heilongjiang, 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