<scp>MAFF</scp> Suppresses Necroptosis in Pancreatic Cancer via the <scp>GATA4</scp> ‐ <scp>MLKL</scp> Axis

Pancreatic adenocarcinoma (PAAD) is a highly aggressive malignancy characterized by rapid progression. In this study, we identify the small MAF protein, MAFF, as a critical driver of PAAD tumorigenesis and a negative regulator of the necroptotic pathway. MAFF silencing significantly suppressed malignant phenotypes in PAAD cells in vitro and attenuated overall tumor growth in vivo, while ectopic expression promoted tumor progression. Mechanistically, RNA-sequencing and Gene Set Enrichment Analysis (GSEA) identified necroptosis as a key pathway suppressed by MAFF. We established that MAFF acts as a direct transcriptional repressor of GATA4, which in turn serves as a transcriptional activator of the necroptotic executioner MLKL. Consequently, MAFF depletion leads to the reactivation of the GATA4-MLKL axis, triggering necroptotic cell death. The growth-inhibitory effects of MAFF silencing were effectively reversed by pharmacological inhibition of necroptosis or genetic knockdown of GATA4 or MLKL. Analysis of clinical data from TCGA and GTEx databases revealed that MAFF is significantly overexpressed in human PAAD tissues compared to normal controls, with elevated levels correlating with advanced histological grade and poor patient prognosis. Collectively, our findings demonstrate that MAFF facilitates PAAD progression by suppressing GATA4-mediated necroptosis, highlighting the MAFF-GATA4-MLKL axis as a promising therapeutic target and prognostic biomarker in pancreatic cancer.