肺癌是最常见的恶性肿瘤之一。尽管经过数十年的研究，肺癌的治疗仍然具有挑战性。非小细胞肺癌（NSCLC）是肺癌的主要类型，也是肺癌治疗研究的重点。去泛素酶泛素特异性蛋白酶 28 (USP28) 在多种肿瘤的进展中发挥作用，并可作为潜在的治疗靶点。本研究旨在确定 USP28 在 NSCLC 进展中的作用。我们研究了 USP28 抑制剂 AZ1 对非小细胞肺癌细胞周期、细胞凋亡、DNA 损伤反应和细胞免疫原性的影响。我们观察到 AZ1 和 siUSP28 诱导 DNA 损伤，导致 Noxa 介导的线粒体凋亡的激活。 DNA损伤和线粒体凋亡释放的dsDNA和mtDNA通过cGAS-STING信号通路激活肿瘤细胞的免疫原性。同时，靶向 USP28 会促进 c-MYC 降解，导致细胞周期停滞并抑制 DNA 修复。这进一步促进了Noxa蛋白介导的DNA损伤诱导的细胞凋亡，从而增强了dsDNA和mtDNA介导的肿瘤细胞免疫原性。此外，我们发现AZ1和顺铂（DDP）联合可以增强治疗效果，从而为克服NSCLC顺铂耐药性提供新策略。这些发现表明，靶向 USP28 并将其与顺铂联合是治疗 NSCLC 的可行策略。© 2024。作者。

Lung cancer is one of the most common malignant tumors. Despite decades of research, the treatment of lung cancer remains challenging. Non-small cell lung cancer (NSCLC) is the primary type of lung cancer and is a significant focus of research in lung cancer treatment. The deubiquitinase ubiquitin-specific protease 28 (USP28) plays a role in the progression of various tumors and serves as a potential therapeutic target. This study aims to determine the role of USP28 in the progression of NSCLC. We examined the impact of the USP28 inhibitor AZ1 on the cell cycle, apoptosis, DNA damage response, and cellular immunogenicity in non-small cell lung cancer. We observed that AZ1 and siUSP28 induce DNA damage, leading to the activation of Noxa-mediated mitochondrial apoptosis. The dsDNA and mtDNA released from DNA damage and mitochondrial apoptosis activate tumor cell immunogenicity through the cGAS-STING signaling pathway. Simultaneously, targeting USP28 promotes the degradation of c-MYC, resulting in cell cycle arrest and inhibition of DNA repair. This further promotes DNA damage-induced cell apoptosis mediated by the Noxa protein, thereby enhancing tumor cell immunogenicity mediated by dsDNA and mtDNA. Moreover, we found that the combination of AZ1 and cisplatin (DDP) can enhance therapeutic efficacy, thereby providing a new strategy to overcome cisplatin resistance in NSCLC. These findings suggest that targeting USP28 and combining it with cisplatin are feasible strategies for treating NSCLC.© 2024. The Author(s).