ZDHHC9, encoding Zinc Finger DHHC-Type Containing 9 protein, functions as a palmitoyltransferase. Palmitoylation, a protein post-translational modification it mediates, is involved in various signaling pathways, influencing protein stability, subcellular localization, and membrane transport, which are crucial for normal cellular functions and disease-related processes [5].

In cancer, ZDHHC9 has been shown to play oncogenic roles. In bladder cancer, its knockdown inhibits tumor proliferation, promotes apoptosis, and enhances chemotherapy efficacy. It acts by palmitoylating Bip protein at Cys420, inhibiting the unfolded protein response [1]. In colon cancer, ZDHHC9 promotes tumor growth by upregulating PD-L1 expression and inhibiting CD8+ T cell function. Its inhibition promotes cancer cell proliferation in vitro but decreases growth in vivo, and enhances CD8+ T cell-mediated cytotoxicity [3]. In pancreatic cancer, knockdown of ZDHHC9 suppresses tumor progression, modifies the tumor microenvironment from immunosuppressive to pro-inflammatory, and sensitizes anti-PD-L1 immunotherapy in a CD8+ T cell-dependent manner [4]. In lung adenocarcinoma, ZDHHC9 deficiency inhibits cell proliferation, migration, and invasion, while promoting apoptosis. ZDHHC9 knockdown reduces PD-L1 palmitoylation, leading to its degradation and enhanced anti-tumor immunity [7]. In glioblastoma, knockout of DHHC9 (ZDHHC9) abrogates GLUT1 palmitoylation and its plasma membrane distribution, impairing glycolysis, cell proliferation, and tumorigenesis [6].

In heart-related function, zDHHC9 palmitoylates Rab3gap1 in cardiomyocytes, leading to changes in Rab3a activity and limiting atrial natriuretic peptide release, which may be relevant for heart failure treatment [2].

In T2DM-related osteogenesis, Zdhhc9 knockdown in MC3T3-E1 cells and T2DM mice improves osteoblast function and peri-implant osteogenesis by regulating mitochondria-associated endoplasmic reticulum membranes (MAMs) through PKG1 palmitoylation [8].

In summary, ZDHHC9 plays diverse and significant roles in multiple biological processes and disease conditions. Through gene knockout or knockdown models in various in vivo studies, it has been revealed as an important factor in cancer development, heart-related peptide secretion, and T2DM-associated osteogenesis. These findings suggest ZDHHC9 could be a potential therapeutic target for these diseases.