Salidroside decreases lipid abundance, mitochondrial function, and expression of the mitochondrial citrate transporter SLC25A1 via miR-1343-3p in gastric cancer

To investigate the potential mechanisms by which salidroside regulates mitochondrial function, SLC25A1 expression, and lipid abundance in gastric cancer (GC) cells via miR-1343-3p. Transcriptome sequencing was performed on MGC-803 cells before and after salidroside treatment to identify differentially expressed miRNAs and mRNAs. Bioinformatic analysis was then used to screen for candidate molecules. The interaction between miR-1343-3p and SLC25A1 was validated by dual-luciferase reporter assay, sequence alignment, and RNA immunoprecipitation (RIP). Mitochondrial morphology and function were examined by transmission electron microscopy and fluorescent probes. MGC-803 and AGS cells were used to assess the effects of salidroside, miR-1343-3p modulation, and SLC25A1 silencing on mitochondrial citrate export, lipid abundance, and cell proliferation. Furthermore, a nude mouse xenograft model was established to evaluate the effects of salidroside and a miR-1343-3p agomir on tumor growth, the expression of miR-1343-3p and SLC25A1, and tumor metabolic status. Transcriptome sequencing revealed 44 differentially expressed miRNAs and 1,384 differentially expressed mRNAs in MGC-803 cells following salidroside treatment. Among them, miR-1343-3p was significantly upregulated as a tumor-suppressive miRNA, while SLC25A1, a mitochondrial citrate transporter, was significantly downregulated. RT-qPCR and Western blot results demonstrated that salidroside significantly increased the expression of miR-1343-3p while decreasing the mRNA and protein expression of SLC25A1. Dual-luciferase reporter, sequence alignment, and RIP assays confirmed that miR-1343-3p directly targets SLC25A1. Further studies showed that salidroside treatment, miR-1343-3p overexpression, and SLC25A1 silencing could all cause the accumulation of mitochondrial citrate, reduced mitochondrial membrane potential, increased ROS production, and decreased the levels of NADH, ATP, acetyl-CoA, free fatty acids, cholesterol, and triglycerides, while significantly inhibiting GC cell proliferation. However, after knocking down miR-1343-3p, the opposite results were observed, which were efficiently rescued by salidroside. In vivo, both salidroside treatment and the miR-1343-3p agomir administration significantly reduced tumor volume and weight. Tumor tissues from these groups showed increased miR-1343-3p expression, decreased SLC25A1 expression, and lipid metabolic changes consistent with those observed in vitro. Salidroside inhibits GC cell proliferation and tumor growth by upregulating the tumor-suppressive miR-1343-3p, which directly targets and downregulates the mitochondrial citrate transporter SLC25A1. Meanwhile, decreased mitochondrial citrate export, impaired mitochondrial function, and reduced lipid abundance are observed. These findings indicate that miR-1343-3p and SLC25A1 may be promising therapeutic targets for metabolic intervention in gastric cancer.