Cancer & Metabolism
·
2025
·Vol. 13
·期 1
·1-17
·
IF 5.3
Li Hao,Gong Tingyue,Zhao Yongheng,Luo Yang,Tang Shuibin,Wang Tingfeng,Lin Haiping,Zhong Ming
Purpose Cancer cells rely on serine biosynthesis for growth, but its regulation in colorectal cancer (CRC) remains not well understood. This study identifies the m 5 C methyltransferase NSUN2 (NOP2/Sun domain family, member 2) as a key regulator of serine biosynthesis, revealing a novel mechanism driving CRC progression. Methods The expression and prognostic value of NSUN2 were evaluated using bioinformatics analyses and immunohistochemistry (IHC) assays. The effects of NSUN2 on cellular serine biosynthesis, intracellular reactive oxygen species (ROS) levels, and apoptosis levels were analyzed both in vitro and in vivo. Additionally, RNA sequencing, Methylated RNA Immunoprecipitation sequencing (MeRIP-seq), RNA immunoprecipitation (RIP), and RNA stability assays were utilized to screen and validate the association between NSUN2 and phosphoglycerate dehydrogenase (PHGDH). Results NSUN2 was found to be highly expressed in CRC and associated with poor patient survival. PHGDH, a direct downstream target of NSUN2, plays a crucial role in NSUN2-mediated serine biosynthesis. Furthermore, inhibition of NSUN2 significantly reduced the intracellular NADH/NAD + and NADPH/NADP + ratios, leading to an increase in ROS levels and apoptosis levels, thereby inhibiting CRC progression. Additionally, NSUN2 enhances PHGDH expression and mRNA stability by binding to the “reader” protein m 5 C-Aly/REF export factor (ALYREF). Conclusions This study identified a novel NSUN2/ALYREF/m 5 C-PHGDH axis might be promising therapeutic targets for CRC.
研究领域:
肿瘤学
·
分子生物学
·
癌症研究
·
RNA生物学
·
代谢调控
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2021
·
IF 11.614
Chen Chen,Tianyu Zhu,Xiaoqin Liu,Dongrong Zhu,Yi Zhang,Sifang Wu,Chao Han,Hao Zhang,Jianguang Luo,Lingyi Kong
The first rate-limiting enzyme of the serine synthesis pathway (SSP), phosphoglycerate dehydrogenase (PHGDH), is hyperactive in multiple tumors, which leads to the activation of SSP and promotes tumorigenesis. However, only a few inhibitors of PHGDH have been discovered to date, especially the covalent inhibitors of PHGDH. Here, we identified withangulatin A (WA), a natural small molecule, as a novel covalent inhibitor of PHGDH. Affinity-based protein profiling identified that WA could directly bind to PHGDH and inactivate the enzyme activity of PHGDH. Biolayer interferometry and LC–MS/MS analysis further demonstrated the selective covalent binding of WA to the cysteine 295 residue (Cys295) of PHGDH. With the covalent modification of Cys295, WA blocked the substrate-binding domain (SBD) of PHGDH and exerted an allosteric effect to induce PHGDH inactivation. Further studies revealed that with the inhibition of PHGDH mediated by WA, the glutathione synthesis was decreased and intracellular levels of reactive oxygen species (ROS) were elevated, leading to the inhibition of tumor proliferation. This study indicates WA as a novel PHGDH covalent inhibitor, which identifies Cys295 as a novel allosteric regulatory site of PHGDH and holds great potential in developing anti-tumor agents for targeting PHGDH.
研究领域:
癌症生物学
·
药理学
·
化学生物学
·
蛋白质组学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY
·
2026
·Vol. 40
·期 8
·e71024
·
IF 3.6
Xueru Wang,Na Luo,Yonggang Ma,Hui Zou,Xishuai Tong,Jiaqiao Zhu,Ruilong Song,Hongyan Zhao,Zongping Liu
Cadmium (Cd) is a widespread environmental contaminant that impairs male reproductive function; however, the metabolic mechanisms underlying Cd‐induced testicular toxicity remain incompletely understood. This study investigated whether serine supplementation could alleviate Cd‐induced testicular injury and explored its association with phosphoglycerate mutase 1 (PGAM1)‐ and phosphoglycerate dehydrogenase (PHGDH)‐related serine metabolism. Forty male C57BL/6 mice were randomly assigned to four groups and received ultrapure water, serine (50 g/L), Cd (50 mg/L), or Cd plus serine in drinking water for 18 weeks. Testicular morphology, hormone levels, ion homeostasis, oxidative stress, inflammation, glycolytic metabolism, fibrosis, apoptosis, and the expression of PGAM1/PHGDH‐related proteins were evaluated. Cd exposure induced marked testicular injury, characterized by reduced testicular weight and index, disrupted reproductive hormone levels, histopathological damage, ion imbalance, oxidative stress, inflammatory responses, and decreased expression of blood–testis barrier‐associated proteins. Cd also suppressed glycolysis and serine biosynthesis, as evidenced by reduced activities of glycolytic enzymes, decreased lactate and pyruvate production, lower serine levels, inhibited PHGDH, PSAT1, and PSPH expression, and altered PGAM1 expression. These changes were accompanied by increased fibrosis and germ cell apoptosis. Serine supplementation substantially ameliorated these abnormalities, restoring metabolic homeostasis, improving antioxidant capacity, reducing inflammation, and attenuating fibrosis and apoptosis. In conclusion, serine exerts a strong protective effect against Cd‐induced male reproductive toxicity by counteracting metabolic dyshomeostasis, highlighting its potential therapeutic value as a beneficial additive against heavy metal‐associated reproductive damage. Serine mitigates cadmium‐induced testicular injury in mice by inhibiting the PGAM1/PHGDH pathway, restoring ion homeostasis and glycolysis, and relieving oxidative stress, inflammation, fibrosis, and apoptosis.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR CELL
·
2024
·
IF 14.5
Chuanlong Wang,Qingyi Chen,Siyuan Chen,Lijuan Fan,Zhending Gan,Muyang Zhao,Lexuan Shi,Peng Bin,Guan Yang,Xihong Zhou,Wenkai Ren
Serine metabolism is involved in the fate decisions of immune cells; however, whether and how de novo serine synthesis shapes innate immune cell function remain unknown. Here, we first demonstrated that inflammatory macrophages have high expression of phosphoglycerate dehydrogenase (PHGDH, the rate-limiting enzyme of de novo serine synthesis) via nuclear factor κB signaling. Notably, the pharmacological inhibition or genetic modulation of PHGDH limits macrophage interleukin (IL)-1β production through NAD+ accumulation and subsequent NAD+-dependent SIRT1 and SIRT3 expression and activity. Mechanistically, PHGDH not only sustains IL-1β expression through H3K9/27 acetylation-mediated transcriptional activation of Toll-like receptor 4 but also supports IL-1β maturation via NLRP3-K21/22/24/ASC-K21/22/24 acetylation-mediated activation of the NLRP3 inflammasome. Moreover, mice with myeloid-specific depletion of Phgdh show alleviated inflammatory responses in lipopolysaccharide-induced systemic inflammation. This study reveals a network by which a metabolic enzyme, involved in de novo serine synthesis, mediates post-translational modifications and epigenetic regulation to orchestrate IL-1β production, providing a potential inflammatory disease target.
研究领域:
免疫学
·
代谢
·
炎症
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）