GRAMD4 (GRAM domain containing 4) is a mitochondrial protein with dual roles in apoptosis and immune regulation. As a pro-apoptotic mediator, GRAMD4 promotes cell death through p73-dependent and p53-independent pathways 1. GRAMD4 translocates to mitochondria where it interacts with Bcl-2, promotes Bax oligomerization, and induces mitochondrial membrane permeabilization with cytochrome c release 1. In hepatocellular carcinoma, GRAMD4 recruits the E3 ligase ITCH to ubiquitinate and degrade TAK1, suppressing MAPK and NF-κB signaling and inhibiting tumor metastasis 2. Regarding immune function, GRAMD4 negatively regulates TLR9-mediated innate immunity by interacting with the ER-resident protein Nogo-B and suppressing TLR9 endolysosomal localization 3. In renal cell carcinoma, circular RNA circGRAMD4 promotes immune evasion by stabilizing NBR1 mRNA through RBM4 interaction, leading to MHC-I degradation and CD8+ T cell dysfunction 4. Clinically, GRAMD4 appears relevant to multiple conditions. In Phelan-McDermid syndrome, GRAMD4 is a candidate gene within the 22q13.3 deletion region contributing to phenotypic severity 5. GRAMD4 shows HPV16-associated methylation alterations in head and neck squamous cell carcinomas 6, and aberrant DNA methylation of GRAMD4 correlates with systemic immune dysregulation in hidradenitis suppurativa 7.