Interdisciplinary Medicine
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2025
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IF 13.6
Liping Yang,Fangli Liao,Yanran Tong,Tong Huang,Yan-e Du,Siyang Wen,Linshan Jiang,Lanlang Peng,Hua Sun,Gaoli Zhang,Weixian Chen
Cancer stem cells exhibit flexible metabolic profiles. However, the underlying mechanisms for differential metabolic pathways affecting stemness maintenance in gastric cancer are poorly understood. Here, we reveal the role of serine hydroxymethyltransferase-2 (SHMT2)/serine-mediated crosstalk between one-carbon metabolism and lipid metabolism in the stemness maintenance of gastric cancer. Clinically, SHMT2 was significantly highly expressed in Gastric cancer cells (GCs) and gastric cancer stem cells, and was associated with clinical malignant features and poor prognosis in gastric cancer patients. Mechanistically, inhibition of SHMT2 expression resulted in diminished serine levels in one-carbon metabolism, which subsequently modified the composition and fluidity of membrane phospholipids, leading to a reduction in lipid rafts within cellular membranes. The remodeling of membrane phospholipids hindered the localization of γ-secretase to lipid rafts, thereby inhibiting the cleavage of CD44 and the subsequent production of CD44-ICD. Consequently, the transcriptional regulation of c-Myc and KLF4 by CD44-ICD was reduced, ultimately disrupting the maintenance of stemness in gastric cancer cells. Together, these results provide compelling evidence for the metabolic adaptability of cancer stem cells, and the SHMT2/serine/lipid rafts signaling axis holds promise as a potential biomarker for the diagnosis and prognosis of gastric cancer. Furthermore, we synthesized HA-Exo-si SHMT2 to investigate targeted therapy for GC, offering a novel approach for the clinical treatment of gastric cancer.
研究领域:
生物化学
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分子生物学
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肿瘤学
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DOI
高影响因子
BIOORGANIC CHEMISTRY
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2025
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IF 4.7
Hafiz Muhammad Bilal Akram,Yulin Liu,Jianshu Dong,Xueke Zhao,Lidong Wang,Wen Zhao,Hongmin Liu,Liying Ma,Cong Han
Esophageal cancer has been regarded as a serious malignancy due to its poor prognosis and high mortality rate. Serine hydroxymethyltransferase 2 (SHMT2) is emerging as an attractive target for esophageal cancer therapy. Compound W478 was identified as a potent SHMT2 inhibitor with an IC 50 value of 1.21 μM, especially whose chemical structure is distinct from the reported SHMT2 inhibitors. Both cellular thermal shift assay and isothermal titration calorimetry experiments showed that compound W478 tightly bound to SHMT2 (K D = 10.6 ± 1.2 μM). The molecular docking analysis revealed its binding at the folate binding site of SHMT2. Moreover, compound W478 exhibited a significant antiproliferative effect on human esophageal cancer cell lines, KYSE-450 and KYSE-70 cells (IC 50 = 1.62 μM, 1.18 μM, respectively). The wound healing and transwell assays showed that compound W478 could inhibit the migratory and invasive potential of KYSE-450 and KYSE-70 cells in a dose-dependent manner. Further studies demonstrated that compound W478 could induce cell arrest at the G2/M phase and promote cell apoptosis and ROS production in KYSE-450 and KYSE-70 cells. These findings indicated that compound W478 could serve as a promising lead compound for the development of SHMT2 inhibitor to address esophageal carcinoma.
研究领域:
肿瘤学
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分子生物学
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药物化学
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转化医学
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细胞生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2025
·Vol. 26
·期 11
·5280
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IF 4.9
Hongjuan Cui,Yan Zhao,Wei Li,Huanjie Cui,Jiahong Han,Enbo Cai
Formononetin is widely used in anti-tumor research, but its poor water solubility leads to low absorption and poor utilization efficiency in vivo, limiting further development. The triphenylphosphine cation was partially attached to the 7-position hydroxyl group of formononetin to specifically target it into the mitochondria of tumor cells to enhance the anti-tumor effect. Detailed structural characterization via 1 H-NMR and 13 C-NMR analysis confirmed the physical properties and chemical structures of 21 newly synthesized derivatives. The effects of these derivatives on tumor cells were assessed by in vitro and computational methods. MTT results from four tumor cell lines showed that formononetin derivatives containing triphenylphosphine had stronger anti-tumor activity than formononetin and exhibited more cytotoxic effects in cancer cells than in normal cells. In particular, the final product 2c (IC 50 = 12.19 ± 1.52 μM) showed more potent anti-tumor activity against A549 cells. It was also superior to formononetin and 5-FU. To identify the potential biological targets, the core-expressed gene SHMT2 in lung cancer mitochondria was screened using network pharmacology technology, and molecular docking analysis confirmed the stable binding of the end products to the amino acid residues of the core genes through the formation of hydrogen bonds and via other interactions. In addition, molecular docking simulations further confirmed that the end product exhibited excellent stability when bound to SHMT2 . These results suggest that triphenylphosphine-containing formononetin derivatives are worthy of further exploration in the search for novel drug candidates for the treatment of cancer.
研究领域:
药理学
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肿瘤学
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计算生物学
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DOI
PubMed
高影响因子
Advanced Science
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2026
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IF 14.1
Tong Yang,Chong Qiu,Yulei Li,Ying Zhang,Chen Wang,Jie Zhou,Zheng Chu,Ang Ma,Ling Huang,Yin Kwan Wong,Junzhe Zhang,Peng Gao,Cui Liu,Junhua Zhang,Huan Tang,Jigang Wang
Triple-negative breast cancer (TNBC) is an aggressive subtype lacking targeted therapies due to the absence of hormone receptors and HER2 expression, resulting in poor clinical outcomes and limited treatment options. Identifying novel vulnerabilities is therefore critical to advancing TNBC therapeutics. Mitochondrial metabolism has emerged as a key regulator of cancer cell survival and proliferation, with serine hydroxymethyltransferase 2 (SHMT2) playing a central role in mitochondrial one-carbon metabolism by supplying one-carbon units for nucleotide biosynthesis and maintaining redox homeostasis. Despite its established importance in cancer metabolism, the functional role and therapeutic potential of SHMT2 in TNBC remain underexplored. Here, we demonstrate that gambogic acid (GA), a natural product with reported anticancer properties, exerts potent and selective cytotoxicity against TNBC cells by covalently targeting SHMT2. GA binds specifically to the critical cysteine residue Cys241, inhibiting SHMT2 enzymatic activity and disrupting mitochondrial function. This leads to bioenergetic collapse, activation of the Nrf2/HO-1 axis, iron overload, and induction of ferroptosis, a non-apoptotic form of cell death increasingly recognized for its therapeutic potential. Our integrative chemoproteomic and mechanistic studies reveal a novel SHMT2-mitochondria-Nrf2/HO-1-ferroptosis axis driving GA's anti-TNBC activity. Moreover, SHMT2 overexpression in TNBC correlates with tumor aggressiveness and poor prognosis, underscoring its role as a metabolic oncogene and promising drug target. These findings establish GA as a novel covalent SHMT2 inhibitor and provide a new framework for exploiting metabolic vulnerabilities to overcome TNBC treatment resistance.
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DOI
高影响因子
JOURNAL OF BIOLOGICAL CHEMISTRY
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2023
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IF 4.8
Yanjie Gao,Bingfeng Zheng,Shuaiqi Xu,Zhibo Zhao,Wanyue Liu,Tingyu Wang,Manman Yuan,Xueqing Sun,Yang Tan,Qiang Xu,Xingxin Wu
Sustainable TGF-β1 signaling drives organ fibrogenesis. However, the cellular adaptation to maintain TGF-β1 signaling remains unclear. In this study, we revealed that dietary folate restriction promoted the resolution of liver fibrosis in mice with nonalcoholic steatohepatitis (NASH). In activated hepatic stellate cells (HSCs), folate shifted toward mitochondrial metabolism to sustain TGF-β1 signaling. Mechanistically, nontargeted metabolomics screening identified that α-linolenic acid (ALA) is exhausted by mitochondrial folate metabolism in activated HSCs. Knocking down serine hydroxymethyltransferase 2 (SHMT2) increases the bioconversion of ALA to docosahexaenoic acid (DHA) which inhibits TGF-β1 signaling. Finally, blocking mitochondrial folate metabolism promoted liver fibrosis resolution in NASH mice. In conclusion, mitochondrial folate metabolism/ALA exhaustion/TGF-βR1 reproduction is a feedforward signaling to sustain profibrotic TGF-β1 signaling and targeting mitochondrial folate metabolism is a promising strategy to enforce liver fibrosis resolution.
研究领域:
肝病学
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分子生物学
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代谢学
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DOI
PubMed
高影响因子
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