Background: BATF2, also known as SARI, has been implicated in tumor progression. However, its role, underlying mechanisms, and prognostic significance in human gastric cancer (GC) are elusive. Methods: We obtained GC tissues and corresponding normal tissues from 8 patients and identified BATF2 as a downregulated gene via RNA-seq. qRT-PCR and western blotting were applied to examine BATF2 levels in normal and GC tissues. The prognostic value of BATF2 was elucidated using tissue microarray and IHC analyses in two independent GC cohorts. The functional roles and mechanistic insights of BATF2 in GC growth and metastasis were evaluated in vitro and in vivo. Results: BATF2 expression was significantly decreased in GC tissues at both the mRNA and protein level. Multivariate Cox regression analysis revealed that BATF2 was an independent prognostic factor and effective predictor in patients with GC. Low BATF2 expression was remarkably associated with peritoneal recurrence after curative gastrectomy. Moreover, elevated BATF2 expression effectively suppressed GC growth and metastasis in vitro and in vivo. Mechanistically, BATF2 binds to p53 and enhances its protein stability, thereby inhibiting the phosphorylation of ERK. Tissue microarray results indicated that the prognostic value of BATF2 was dependent on ERK activity. In addition, the N6-methyladenosine (m 6 A) modification of BATF2 mRNA by METTL3 repressed its expression in GC. Conclusions: Collectively, our findings indicate the pivotal role of BATF2 in GC and highlight the regulatory function of the METTL3/BATF2/p53/ERK axis in modulating GC progression, which provides potential prognostic and therapeutic targets for GC treatment.

Iron plays a crucial role in many physiological processes of the human body, but iron is continuously deposited in the brain as we age. Early studies found iron overload is directly proportional to cognitive decline in Alzheimer’s disease (AD). Amyloid precursor protein (APP) and tau protein, both of which are related to the AD pathogenesis, are associated with brain iron metabolism. A variety of iron metabolism-related proteins have been found to be abnormally expressed in the brains of AD patients and mouse models, resulting in iron deposition and promoting AD progression. Amyloid β (Aβ) and hyperphosphorylated tau, two pathological hallmarks of AD, can also promote iron deposition in the brain, forming a vicious cycle of AD development-iron deposition. Iron deposition and the subsequent ferroptosis has been found to be a potential mechanism underlying neuronal loss in many neurodegenerative diseases. Iron chelators, antioxidants and hepcidin were found useful for treating AD, which represents an important direction for AD treatment research and drug development in the future. The review explored the deep connection between iron dysregulation and AD pathogenesis, discussed the potential of new hypothesis related to iron dyshomeostasis and ferroptosis, and summarized the therapeutics capable of targeting iron, with the expectation to draw more attention of iron dysregulation and corresponding drug development.

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