Ethanol Extract of Huang-Jin-Shuang-Shen Enhances Oxaliplatin Responses in Gastric Cancer Models: Associations with FBLN1 and Mitochondrial Dysfunction

AbstractBackground: Oxaliplatin (OXA) remains the clinical cornerstone for advanced gastric cancer (GC), but compensatory DNA repair and apoptotic evasion severely limit its long-term efficacy.Objectives: This study investigated the capacity of Huang-Jin-Shuang-Shen ethanol extract (HJSS-E) to reverse OXA resistance and delineated its underlying molecular mechanisms.Methods: Direct targets were identified via DARTS-proteomics combined with TCGA analysis. Downstream signaling networks were validated using transcriptomics, JC-1/Rhod-2 AM probes, patient-derived organoids (PDOs), xenografts, and spatial single-cell multiplex immunofluorescence (mIF).Results: HJSS-E robustly enhanced OXA sensitivity by compounding DNA double-strand breaks. FBLN1 was identified as the direct pharmacological target of HJSS-E. Mechanistically, HJSS-E binding to FBLN1 relieved its negative regulation on RYR2, leading to the downregulation of SIRT3. This disruption provoked a catastrophic influx of endoplasmic reticulum calcium into mitochondria, triggering transmembrane potential depolarization and an energetic crisis characterized by massive ATP and NAD⁺ depletion. Spatial mIF and PDO platforms confirmed that FBLN1 expression dictates oxaliplatin resistance and spatial cell-fate decisions. Furthermore, Salvianolic acid A (SAA) was verified as the primary active monomer binding FBLN1 to fully recapitulate HJSS-E’s chemo-sensitizing effects.Conclusions: HJSS-E and SAA act as sensitizers for oxaliplatin in GC by disrupting the FBLN1/RYR2/SIRT3 axis, engineering a lethal mitochondrial calcium crisis that starves tumor cells of the energetic substrates indispensable for DNA damage repair.