JOURNAL OF BIOLOGICAL CHEMISTRY
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2025
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IF 3.9
Yijun Yang,Nengyi Wang,Yuankun Chen,Tianpeng Ma,Minhua Weng,Haifeng Wu,Qiuping Wu,Yiqiang Xie,Chuanwu Zhu,Wenting Li
Nonalcoholic fatty liver disease (NAFLD) has posed a huge threat to public health globally, but there are currently no approved drugs available. Growing evidence has proved the close association between increased Th17 cells and NAFLD progression. Interleukin-4 induced protein 1 (IL4I1), an amino acid oxidase secreted by immune cells, was reported to regulate the Th17 cells, but its exact role in NAFLD progression has not been fully explained yet. We found that IL4I1 was highly expressed in the liver of C57BL/6J mice with NAFLD induced by an 8-weeks western diet. To explore the IL4I1’s effect, mice were injected with AAV8 encoding IL4I1 1 week before western diet administration. The results showed that IL4I1 overexpression inhibited the NAFLD progression, demonstrated by relieved liver damage and lipid accumulation. The underlying mechanism in which IL4I1 acts on NAFLD might be attributed to the inactivated AKT/forkhead box protein O1 (FOXO1) signaling pathway–mediated decrease of Th17 cells in liver tissues. Subsequently, by culturing naive CD4 + T cells isolated from the spleen of mice in Th17 cell-polarizing conditions, we determined that IL4I1 overexpression inhibited Th17 cell differentiation by inactivating the AKT/FOXO1 pathway, whereas its knockdown exhibited opposite effects. Further, the AKT activator SC79 reversed the effect of IL4I1 overexpression on Th17 cell differentiation. Collectively, our study supports that compensatory upregulation of IL4I1 protects against liver damage and lipid accumulation in NAFLD progression, partially by inhibiting the activated AKT/FOXO1 signaling pathway-induced Th17 cell differentiation.
研究领域:
免疫学
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肝病学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2025
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IF 14.1
Zhaoxuan Wang,Weijiao Xu,Lei Zhao,Lin Zhong,Wendan Yu,Shengmin Wang,Lu Sun,Tao Guo,Fengzhou Li,Zhuoshi Li,Lei Fang,Shiqing Wang,Guohui Zhang,Guoqing Xue,Wei Guo,Shilei Zhao,Chundong Gu
Lung adenocarcinoma (LUAD) displays marked intratumoral heterogeneity with distinct histological patterns. The solid pattern representing poorly differentiated LUAD is linked to poor prognosis and therapeutic resistance. To uncover underlying mechanisms, we integrate bulk and single-cell RNA sequencing and identify a preferential enrichment of interleukin 4 induced 1 (IL4I1)-expressing tumor-associated macrophages (TAMs) and tryptophan 2,3-dioxygenase (TDO2)-expressing myofibroblastic cancer-associated fibroblasts (myCAFs) in a solid pattern of LUAD. Spatial transcriptomics reveals their co-localization in peritumoral stroma, forming an immune-excluded niche. Mechanistically, TDO2⁺ myCAFs promoted monocyte-to-IL4I1⁺ TAM differentiation via the kynurenine-aryl hydrocarbon receptor (AhR) axis. Tryptophan metabolomic landscapes confirm that IL4I1⁺ TAMs and TDO2⁺ myCAFs enhance tryptophan degradation and accumulation of AhR ligands (e.g., kynurenine, indole-3-carboxaldehyde), contributing to CD8⁺ T cell exhaustion and anti-PD-1 therapeutic resistance. IL4I1⁺ TAMs and TDO2⁺ myCAFs conformably mediate ferroptosis resistance through the AhR-NRF2-GPX4-SLC7A11 pathway. Notably, AhR antagonist CH-223191 restores ferroptosis sensitivity of tumor cells. A triple therapy combining CH-223191, ferroptosis inducer (Imidazole ketone erastin or RSL3), and anti-PD-1 agent demonstrates superior efficacy and safety in vivo. Together, our findings demonstrate that IL4I1⁺ TAMs and TDO2⁺ myCAFs synergistically establish an immunosuppressive, ferroptosis-resistant niche via AhR signaling in solid predominant LUAD and offer promising therapeutic strategies to reprogram the tumor microenvironment.
研究领域:
肿瘤学
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免疫学
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分子生物学
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肿瘤微环境
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癌症代谢
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转化医学
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产品关联
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
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2026
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IF 10.4
Li Ju-fei,Wang Hao,Kang Ling,Xu Cheng-cheng,Liu Yuan-chun,Li Zi-xuan,Lin Shao-hao,Wang Ming-zhi,Xu Xiao-min,Wang Pei-pei,Yin Wan-chao,Zhou Yu-bo,Zhou Yu,Li Jia
Metabolic hijacking of tryptophan (Trp) via the IL4I1-AHR axis is a pivotal immune evasion mechanism in cancers, yet therapeutic strategies to disrupt this pathway remain unexplored. Here, we report the identification of ZY-MY-111, a selective small-molecule inhibitor of interleukin-4-induced-1 (IL4I1), through an in-house compound library screening and structural optimization. ZY-MY-111 exhibits potency (IC 50 = 1.86 ± 0.13 μM) in blocking IL4I1-mediated oxidative deamination. Mechanistically, ZY-MY-111 acts as a mixed-type inhibitor, competitively occupying the catalytic pocket of IL4I1 and disrupting Trp-AHR signaling in cells. Functionally, ZY-MY-111 promotes T cell proliferation, enhancing immune responses against the tumor cells. In syngeneic tumor models, ZY-MY-111 achieved 49% tumor growth inhibition in CT26 colon carcinoma ( P < 0.001) and 56% tumor growth inhibition in A20 lymphoma ( P < 0.001) by remodeling the immunosuppressive microenvironment: increasing CD8 + /CD4 + T cell ratios, reducing myeloid-derived suppressor cells (MDSCs, 59% decrease), and enhancing effector memory T cell infiltration. Our findings position IL4I1 inhibition as a potential strategy to restore anti-tumor immunity.
✓ 已验证
DOI
PubMed
高影响因子
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