非小细胞肺癌（NSCLC）是一种高度恶性的肿瘤，治疗选择有限，基于铂的化疗是NSCLC的标准治疗方法，然而常见产生耐药性。NSCLC细胞通过增强的抗氧化防御系统来抵抗过量的活性氧自由基（ROS），这在肿瘤进展和耐药性中起重要作用，但机制尚未完全明确。最近的研究表明组蛋白在肿瘤进展和细胞抗氧化应答中的参与，然而主要组蛋白变异体H1.2（H1C）在NSCLC发展中的作用尚不清楚。本研究证明H1.2在NSCLC肿瘤中的表达增加，并与较差的生存率相关。通过将H1c敲除等位基因与小鼠NSCLC模型（KrasLSL-G12D/+）交叉，发现H1.2敲除抑制了NSCLC的进展，增强了氧化应激，并显著降低了关键抗氧化剂谷胱甘肽（GSH）和GCLC（GSH合成的限速酶催化亚单位）的水平。此外，高表达的H1.2与多种化疗药物的IC50以及接受化疗的NSCLC患者的预后相关。H1.2缺失的NSCLC细胞在顺铂治疗后表现出降低的存活率和增加的ROS水平，而ROS清除剂可消除存活抑制。机制上，H1.2与NRF2（抗氧化应答的主要调节因子）相互作用；H1.2增强了NRF2的核水平和稳定性，并促进了NRF2与GCLC启动子的结合和随后的转录；而NRF2也通过转录上调H1.2的表达。综上所述，这些结果揭示了H1.2在NSCLC中的肿瘤驱动作用，并显示了一个“H1.2-NRF2”抗氧化正反馈循环，促进肿瘤进展和化疗耐药性。

Nonsmall cell lung cancer (NSCLC) is highly malignant with limited treatment options, platinum-based chemotherapy is a standard treatment for NSCLC with resistance commonly seen. NSCLC cells exploit enhanced antioxidant defense system to counteract excessive reactive oxygen species (ROS), which contributes largely to tumor progression and resistance to chemotherapy, yet the mechanisms are not fully understood. Recent studies have suggested the involvement of histones in tumor progression and cellular antioxidant response; however, whether a major histone variant H1.2 (H1C) plays roles in the development of NSCLC remains unclear. Herein, we demonstrated that H1.2 was increasingly expressed in NSCLC tumors, and its expression was correlated with worse survival. When crossing the H1c knockout allele with a mouse NSCLC model (KrasLSL-G12D/+), H1.2 deletion suppressed NSCLC progression and enhanced oxidative stress and significantly decreased the levels of key antioxidant glutathione (GSH) and GCLC, the catalytic subunit of rate-limiting enzyme for GSH synthesis. Moreover, high H1.2 was correlated with the IC50 of multiple chemotherapeutic drugs and with worse prognosis in NSCLC patients receiving chemotherapy; H1.2-deficient NSCLC cells presented reduced survival and increased ROS levels upon cisplatin treatment, while ROS scavenger eliminated the survival inhibition. Mechanistically, H1.2 interacted with NRF2, a master regulator of antioxidative response; H1.2 enhanced the nuclear level and stability of NRF2 and, thus, promoted NRF2 binding to GCLC promoter and the consequent transcription; while NRF2 also transcriptionally up-regulated H1.2. Collectively, these results uncovered a tumor-driving role of H1.2 in NSCLC and indicate an "H1.2-NRF2" antioxidant feedforward cycle that promotes tumor progression and chemoresistance.