Mucolipin TRP Cation Channel 1 Depletion Promotes Gastric Cancer Cell Ferroptosis Through the AKT Pathway

Mucolipin TRP cation channel 1 (MCOLN1), also called TRPML1, drives the progression of various cancers and inhibits ferroptosis in a number of diseases. This study aimed to investigate whether MCOLN1 depletion regulates ferroptosis in gastric cancer and its molecular regulatory crosstalk with the AKT pathway. MCOLN1 siRNA was transferred into AGS and HGC27 cells to deplete MCOLN1 expression. SC79 was added to activate the AKT pathway. The relationship between MCOLN1 and AKT was analyzed via public databases. MCOLN1 depletion reduced glutathione (GSH) but increased malondialdehyde (MDA), reactive oxygen species (ROS), and Fe 2+ levels in both cell lines. MCOLN1 depletion also decreased SLC7A11 expression and increased ACSL4 expression in HGC27 cells but only downregulated SLC7A11 expression in AGS cells. Cell viability decreased after MCOLN1 depletion in both cell lines. The protein–protein interaction network showed potential associations among MCOLN1, TRPC1, TPCN1, and AKT1, with TRPC1 and TPCN1 positioned between MCOLN1 and AKT1 in the network; online public database analysis revealed that MCOLN1 was positively correlated with TRPC1, TPCN1, and AKT1 in gastric cancer tissue samples. Additionally, MCOLN1 depletion decreased p‐AKT expression in both cell lines. Next, SC79 effectively activated the AKT pathway in both cell lines and suppressed ferroptosis. Moreover, AKT activation attenuated the ferroptosis‐promoting effect of MCOLN1 depletion in both cell lines. In conclusion, MCOLN1 depletion promotes gastric cancer cell ferroptosis, at least in part, through inhibition of the AKT pathway. TRPC1 and TPCN1 may be involved in this regulatory axis, but their precise roles remain to be determined.