Work

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

Year: 2026

Type: article

Abstract: Background: Platinum-based chemotherapy, particularly oxaliplatin (OXA), is a primary treatment modality for advanced gastric carcinoma. However, the development of apoptotic resistance and enhanced DNA repair mechanisms frequently compromises its enduring clinical benefit. Objectives: The present research aims to evaluate whether an ethanol extract of Huang-Jin-Shuang-Shen (HJSS-E) can modulate cellular sensitivity to oxaliplatin and to characterize the associated molecular pathways. Methods: Potential interacting proteins were screened through an integration of DARTS-based proteomics and transcriptomic database mining (TCGA). The subsequent biological effects were examined employing RNA sequencing, fluorescent organelle probes (Rhod-2 AM and JC-1), murine tumor models, patient-derived organoids (PDOs), and multiplex immunofluorescence (mIF) at single-cell resolution. Results: HJSS-E enhanced OXA-associated DNA damage and apoptosis in gastric cancer cells and improved treatment responses in xenograft and patient-derived organoid models. Drug Affinity Responsive Target Stability (DARTS) and Cellular Thermal Shift Assay (CETSA) identified Fibulin-1 (FBLN1) as a candidate target. Combination treatment was associated with altered Ryanodine Receptor 2 (RYR2)/Sirtuin 3 (SIRT3) expression, reduced ATP content and NAD+/NADH ratios, and increased mitochondria-associated Rhod-2 fluorescence. Salvianolic acid A (SAA) interacted with recombinant FBLN1 in SPR assays and reproduced selected cellular effects of HJSS-E. Conclusions: HJSS-E potentiates the antitumor efficacy of OXA in preclinical gastric cancer models, accompanied by mitochondrial dysfunction and coordinated alterations in RYR2/SIRT3 expression. FBLN1 emerges as a candidate molecular mediator of this response.

Source: Pharmaceuticals

DOI: 10.3390/ph19111771