Currently, chemotherapy remains occupying a pivotal place in the treatment of pancreatic ductal adenocarcinoma (PDAC). Nonetheless, the emergence of drug resistance in recent years has limited the clinical efficacy of chemotherapeutic agents, especially gemcitabine (GEM). Through bioinformatics analysis, AT-rich Interactive Domain-containing Protein 3A (ARID3A), one of transcription factors, is discovered to possibly participate in this progress. This study thoroughly investigates the potential role of ARID3A in the malignant progression and GEM chemoresistance of PDAC and explores the underlying mechanisms. The results indicate that ARID3A knockdown suppresses tumor development and enhances the sensitivity of PDAC cells to GEM in vitro and vivo. Mechanically, CUT&Tag profiling sequencing, RNA‐sequencing and functional studies demonstrates that decreased ARID3A expression alleviates the transcriptional inhibition of phosphatase and tensin homolog (PTEN), consequently leading to glutathione peroxidase 4 (GPX4) depletion and increased lipid peroxidation levels. Activated ferroptosis induced by the inhibition of GPX4 subsequently restricts tumor progression and reduces GEM resistance in PDAC. This research identifies the ferroptosis regulatory pathway of ARID3A-PTEN-GPX4 axis and reveals its critical role in driving the progression and chemoresistance of pancreatic cancer. Notably, both inhibition of ARID3A and enhancement of ferroptosis can increase chemosensitivity to GEM, which offers a promising opportunity for developing therapeutic strategies to combat acquired chemotherapy resistance in pancreatic cancer.

中文翻译：

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ARID3A通过抑制PTEN诱导的铁死亡增强胰腺癌的化疗耐药性


目前，化疗在胰腺导管腺癌（PDAC）的治疗中仍然占据着关键地位。尽管如此，近年来耐药性的出现限制了化疗药物特别是吉西他滨（GEM）的临床疗效。通过生物信息学分析，发现转录因子之一富含AT的交互结构域蛋白3A（ARID3A）可能参与了这一进程。本研究深入研究了ARID3A在PDAC恶性进展和GEM化疗耐药中的潜在作用，并探讨其潜在机制。结果表明，ARID3A 敲低可抑制肿瘤发展并增强 PDAC 细胞在体外和体内对 GEM 的敏感性。从机械角度来看，CUT&Tag 分析测序、RNA 测序和功能研究表明，ARID3A 表达减少可以减轻磷酸酶和张力蛋白同源物 (PTEN) 的转录抑制，从而导致谷胱甘肽过氧化物酶 4 (GPX4) 消耗和脂质过氧化水平增加。抑制 GPX4 诱导的激活铁死亡随后限制肿瘤进展并降低 PDAC 中的 GEM 抵抗。这项研究确定了 ARID3A-PTEN-GPX4 轴的铁死亡调节途径，并揭示了其在驱动胰腺癌进展和化疗耐药中的关键作用。值得注意的是，抑制 ARID3A 和增强铁死亡都可以增加对 GEM 的化疗敏感性，这为开发对抗胰腺癌获得性化疗耐药的治疗策略提供了一个有希望的机会。