Lu Ting, Wang Qingda, Xin Yuping, Wu Xiaohua, Wang Yang, Xia Yongzhen, Xun Luying, Liu Huaiwei
School of Health and Life Sciences, University of Health and Rehabilitation Sciences Qingdao Hospital (Qingdao Municipal Hospital), University of Health and Rehabilitation Sciences, Qingdao, 266071, People's Republic of China.
State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266200, People's Republic of China.
Redox Biol. 2025 Jun;83:103650. doi: 10.1016/j.redox.2025.103650. Epub 2025 Apr 24.
Colorectal cancer (CRC) exhibits significant diversity and heterogeneity, posing a requirement for novel therapeutic targets. Polysulfides are associated with CRC progression and immune evasion, but the underlying mechanisms are not fully understood. Sulfide: quinone oxidoreductase (SQR), a mitochondrial flavoprotein, catalyzes hydrogen sulfide (HS) oxidation and polysulfides production. Herein, we explored its role in CRC pathogenesis and its potential as a therapeutic target. Our findings revealed that SQR knockout disrupted polysulfides homeostasis, diminished mitochondrial function, impaired cell proliferation, and triggered early apoptosis in HCT116 CRC cells. Moreover, the SQR knockout led to markedly reduced tumor sizes in mice models of colon xenografts. Although the transcription of glycolytic genes remained largely unchanged, metabolomic analysis demonstrated a reprogramming of glycolysis at the fructose-1,6-bisphosphate degradation step, catalyzed by aldolase A (ALDOA). Both Western blot analysis and enzymatic assays confirmed the decrease in ALDOA levels and activity. In conclusion, the study establishes the critical role of SQR in mitochondrial function and metabolic regulation in CRC, with its knockout leading to metabolic reprogramming and diminished tumor growth in HCT116 tumor xenografts. These insights lay a foundation for the development of SQR-targeted therapies for CRC.
结直肠癌（CRC）表现出显著的多样性和异质性，这就需要新的治疗靶点。多硫化物与CRC进展和免疫逃逸相关，但其潜在机制尚未完全明确。硫化物：醌氧化还原酶（SQR）是一种线粒体黄素蛋白，催化硫化氢（HS）氧化和多硫化物生成。在此，我们探究了其在CRC发病机制中的作用及其作为治疗靶点的潜力。我们的研究结果显示，SQR基因敲除破坏了多硫化物稳态，降低了线粒体功能，损害了细胞增殖，并在HCT116 CRC细胞中引发了早期凋亡。此外，SQR基因敲除导致结肠异种移植小鼠模型中的肿瘤大小显著减小。尽管糖酵解基因的转录基本保持不变，但代谢组学分析表明，在醛缩酶A（ALDOA）催化的果糖-1,6-二磷酸降解步骤中，糖酵解发生了重编程。蛋白质印迹分析和酶活性测定均证实了ALDOA水平和活性的降低。总之，该研究确立了SQR在CRC线粒体功能和代谢调节中的关键作用，其基因敲除导致代谢重编程，并减少了HCT116肿瘤异种移植中的肿瘤生长。这些见解为开发针对CRC的SQR靶向疗法奠定了基础。
