KIAA1429 protects hepatocellular carcinoma cells from ferroptotic cell death with a m⁶A-dependent posttranscriptional modification of SLC7A11

N6-methyladenosine (m(6)A) modification represents the most abundant internal methylation of eukaryotic RNAs. KIAA1429 acts as a key component of the m6A methyltransferase complex, but its function and mechanism in ferroptotic cell death of hepatocellular carcinoma (HCC) are barely defined. We found that KIAA1429 suppression triggered ferroptosis in HCC cells according to increased cell death, iron and MDA levels, C11-BODIPY-positive cells, ROS production and decreased GSH level. Ferroptosis inhibitors ferrostatin-1 (0.5 mu M) and liproxstatin-1 (10 mu M) blocked KIAA1429 suppression-induced ferroptosis of HCC cells. In addition, overexpressed KIAA1429 notably heightened the activity of cystine/glutamate antiporter (SLC7A11). SLC7A11 up-regulation partially hindered KIAA1429 inhibition-mediated ferroptosis of HCC cells. The regulation SLC7A11 by KIAA1429 was attenuated by global m6A inhibitor cycloleucine (40 mu M). RNA immunoprecipitation confirmed the binding of KIAA1429 to m(6)A on SLC7A11 transcript. Additionally, it was proven that KIAA1429 inhibition mitigated HCC growth in subcutaneous xenograft mice through SLC7A11. Altogether, our findings first propose that KIAA1429 protects HCC cells from ferroptosis with a m(6)A-dependent post-transcriptional modification of SLC7A11 and offer a novel insight into the dysregulated epi-transcriptomics in the context of HCC.