{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n A growing body of work indicates that α‐protein kinase 2 (ALPK2) plays context‐dependent roles in modulating key cellular processes such as cell cycle progression, DNA repair, apoptosis, and migration. In several cancer models, ALPK2 appears to promote tumor cell proliferation and invasion. For instance, in bladder cancer, ALPK2 is upregulated and its knockdown reduces proliferation, migration and tumor growth through regulation of downstream effectors such as DEPDC1A, suggesting an oncogenic role in disease progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Similar tumor‐promoting functions are observed in renal cell and ovarian carcinomas, where heightened ALPK2 expression correlates with advanced stage and poor prognosis; silencing ALPK2 leads to cell cycle arrest, diminished activity of pathways involving Akt, CDK6, Cyclin D1 and PIK3CA, and enhanced apoptosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In contrast, studies in colorectal contexts indicate that ALPK2 is down‐regulated by oncogenic KRAS and that its normal expression is critical for promoting luminal apoptosis and proper DNA repair gene expression in colonic crypts. Moreover, a germline missense variant in ALPK2 has been associated with an attenuated apoptotic program and a more metastatic phenotype in colorectal adenomas, linking ALPK2 loss‐of‐function to neoplastic progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Additional evidence further supports the multifaceted role of ALPK2 in human disease. In non‐small cell lung cancer cells, ALPK2 is directly regulated by miRNA‐214, implicating it in the control of invasive potential."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Beyond cancer, genetic variants in ALPK2 have been linked to increased risk of liver fibrosis in HIV/HCV coinfected patients and it has emerged as a candidate gene within a blood pressure quantitative trait locus in hypertension models, suggesting that ALPK2 may also influence fibrotic and cardiovascular disease processes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, while ALPK2 is a member of the atypical α‐kinase family—which has been implicated in regulation of intracellular transport, cell migration, and proliferation—a knockout study in mice revealed that ALPK2 is dispensable for cardiac development and function, highlighting species‐ and tissue‐specific differences in ALPK2 biology."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " In another context, a predicted pathogenic variant in ALPK2 was identified in patients with sporadic schwannomatosis, suggesting that aberrations in ALPK2 function may contribute to tumor predisposition in diverse tissues."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Collectively, these studies underscore the versatile and context‐dependent roles of ALPK2 in disease, providing a basis for its further evaluation as a potential diagnostic marker and therapeutic target in cancer and other disorders."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yuchen Wang, Jie Wu, Wenjie Luo, et al. 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