Sorafenib is a tyrosine kinase inhibitor that shows anti-tumour effects against various cancers including gastric cancer (GC). However, the clinical application of sorafenib is often hampered by drug resistance. Sirtuins 6 (SIRT6) is a member of the Sirtuin family of NAD (+)-dependent enzymes that are critically involved in various biological activities. This study presents that SIRT6 silencing overcomes sorafenib resistance by promoting ferroptosis, which is a novel form of cell death. Mechanistically, SIRT6 inhibition led to the inactivation of the Keap1/Nrf2 signalling pathway and downregulation of GPX4. The overexpression of GPX4 or activation of Keap1/Nrf2 reverses the effects of the downregulation of SIRT6 on sorafenib-induced ferroptosis. Thus, targeting the SIRT6/Keap1/Nrf2/GPX4 signalling pathway may be a potential strategy for overcoming sorafenib resistance in GC.

索拉非尼是一种酪氨酸激酶抑制剂，对包括胃癌 (GC) 在内的各种癌症具有抗肿瘤作用。然而，索拉非尼的临床应用往往受到耐药性的阻碍。Sirtuins 6 (SIRT6) 是 NAD (+) 依赖性酶的 Sirtuin 家族的成员，这些酶与各种生物活动密切相关。这项研究表明，SIRT6 沉默通过促进铁死亡（一种新的细胞死亡形式）克服了索拉非尼耐药性。从机制上讲，SIRT6 抑制导致 Keap1/Nrf2 信号通路失活和 GPX4 下调。GPX4 的过表达或 Keap1/Nrf2 的激活逆转了 SIRT6 下调对索拉非尼诱导的铁死亡的影响。因此，