Gastric cancer prognoses are persistently poor due to cancer's penchant to metastasize. As a crucial regulator of signal transducer and activator of transcription (STAT3) signaling, sirtuin 1's (SIRT1) function in gastric cancer has not been well understood. Here, we report upregulated expression of SIRT1 in tissues isolated from gastric cancer patients. However, we show that the depletion of SIRT1‐mediated enhanced cancer cell proliferation and metastasis, and resulted in the enrichment of phosphorylated STAT3, acetylated STAT3, and matrix metalloproteinase 13 (MMP‐13) in both in vivo and in vitro experiments. Additionally, we demonstrate that small interfering RNAs targeting the production of STAT3, AG490, and CL‐821983 in cancer cells depleted of SIRT1 reduce metastasis. Our findings indicate that MMP‐13 expression is associated with lymph node metastasis and poor survival outcomes in gastric cancer patients. In vivo models also showed that depleted SIRT1 promoted gastric cancer growth via the STAT3/MMP‐13 axis. In conclusion, SIRT1 depletion encourages gastric cancer progression through the activation of STAT3/MMP‐13 signaling, suggesting that SIRT1 may function as a tumor suppressor. We postulate that the upregulation of SIRT1 in gastric cancer patients may be the result of a feedback mechanism that aims to oppose the damaging effects of STAT3 signaling. As such, SIRT1 activators could potentially serve as preventive and therapeutic treatments for metastatic gastric cancer.

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