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【第69期】前沿靶點速遞:每周醫學研究精選

日期:2025-12-23 15:20:56


01、靶點:CXCR6
應用:治療銀屑病復發的潛在靶點
來源:CXCR6 sustains TRM-driven psoriasis relapse by CXCL16 chemotaxis and curcumol targeting.J Adv Res,2025 Nov 01
 
圖源:10.1016/j.jare.2025.10.066[1]
 
臺州中心醫院趙朕雄與上海華山醫院杜鵑團隊發現,CXCL16-CXCR6軸介導皮膚TRM細胞滯留是銀屑病復發關鍵;CXCR6敲除顯著減輕炎癥并延緩復發。天然產物莪術醇可靶向抑制CXCR6信號,減少TRM駐留,降低復發率,為防復發提供新策略。


02、靶點:SMAD1
應用:治療結直腸癌靶向治療耐藥的潛在靶點
來源:Paneth-like transition drives resistance todual targeting of KRAS and EGFR in colorectal cancer.Cancer Cell,2025 Nov 13
 
 
圖源:10.1016/j.ccell.2025.10.010[2]

中山大學高益軍、王峰、廖雯婷、趙齊團隊發現,結直腸癌在KRAS/EGFR雙靶治療壓力下可轉分化為類潘氏細胞,SMAD1轉錄因子通過上調FGFR3驅動該譜系可塑性,導致MAPK再激活和耐藥;清除類潘氏細胞或抑制FGFR3可恢復藥物敏感性,為克服非遺傳耐藥提供新策略。


03、靶點:RIOK2
應用:治療感染(尤其是耶爾森菌感染)的潛在靶點
來源:RIOK2 kinase regulates the translocation of the FADD–RIPK1–Caspase-8 complex to the ER and the cleavage of Gasdermin D to drive pyroptosis.Nat Commun,2025 Nov 17
 
圖源:10.1038/s41467-025-65012-7[3]
 
同濟大學戈寶學/王琳團隊發現,RIOK2以激酶活性驅動FADD-RIPK1-Caspase-8復合體從溶酶體遷至內質網,并借ATP酶活性直接觸發Caspase-8切割GSDMD,啟動細胞焦亡;髓系敲除或抑制RIOK2均削弱小鼠抗耶爾森菌能力,揭示其作為感染免疫關鍵“扳機”及潛在抗感染新靶點。


04、靶點:BCL9
應用:肝癌免疫治療耐藥的潛在靶點
來源:Targeting tumor-intrinsic BCL9 reversesimmunotherapy resistance by elicitingmacrophage-mediated phagocytosis andantigen presentation.Nat Commun,2025 Nov 17

 
 
圖源:10.1038/s41467-025-65945-z[4]
 
樊嘉/楊欣榮/朱棣/胡博團隊發現Wnt共激活因子BCL9是肝癌免疫耐藥關鍵“冷”因子,據此設計多肽抑制劑hsBCL9Z96,高選擇性阻斷BCL9/β-catenin互作,半衰期長、毒性低。其通過下調BMP4重塑巨噬細胞M1極化、削弱CD24–SIGLEC-10“別吃我”信號,增強吞噬與抗原呈遞,將TME轉為“熱”狀態;與抗PD-L1聯用顯著克服ICI耐藥,為HCC提供可臨床轉化的先導聯合策略。


05、靶點:FADS
應用:治療肝癌免疫治療耐藥的潛在靶點
來源:FAD synthase confers ferroptosis resistance and restrains CD8+ T cell recruitment in hepatocellular carcinoma.Nat Commun,2025 Oct 29
 
圖源:10.1038/s41467-025-64572-y[5]
 
北京協和醫院趙海濤與徐醫附院呂凌團隊發現,肝癌高表達VB2代謝酶FADS,通過生成FAD維持谷胱甘肽和鐵穩態,增強鐵死亡抗性,并抑制cGAS-STING趨化信號阻礙CD8?T細胞浸潤,導致免疫逃逸和抗PD-1耐藥;FADS抑制劑橙皮苷可逆轉上述效應,為肝癌提供聯合免疫治療新靶點。


06、靶點:TRIM11
應用:治療腫瘤免疫治療(抗PD-1/PD-L1)耐藥的潛在靶點
來源:TRIM11 potentiates antitumor immunity via blocking IFNγ/PD-L1 axis.Cell Death Differ,2025 Nov 07
 
圖源:10.1038/s41418-025-01610-8[6]
 
中山大學陳亮團隊發現E3泛素連接酶TRIM11在IFN-γ刺激下被JAK1磷酸化穩定,轉而通過K63泛素化抑制JAK1-STAT通路,阻斷PD-L1上調,增強CD8?T細胞活性,發揮“熱”腫瘤中的抑癌功能;TRIM11低表達與免疫治療耐藥及預后差相關,提示提升其表達可成為增敏免疫治療的聯合策略。


07、靶點:LRRC8A
應用:治療血管衰老及相關年齡性疾病的潛在靶點
來源:Endothelial LRRC8A Delays Vascular Ageing in Natural and Accelerated Ageing Mouse Models.Cardiovasc Res,2025 Dec 18
 
圖源:10.1093/cvr/cvaf212[7]
 
廈大/廈心醫院張雁惠團隊發現,自然與加速衰老小鼠主動脈內皮富亮氨酸重復蛋白LRRC8A顯著下調;內皮特異性敲除加速全身衰老,機制在于LRRC8A通過激活AMPK促進SIRT1核穿梭抗氧化、抗周期阻滯,口服SIRT1激動劑或AAV9恢復內皮LRRC8A均可逆轉血管衰老,為干預年齡相關慢病提供可靶向LRRC8A-AMPK-SIRT1軸的新策略。


推薦產品

靶點 重組蛋白 貨號
BCL9 Recombinant Human B-cell CLL/lymphoma 9 protein (BCL9), partial CSB-EP002631HU
CXCR6 Recombinant Human C-X-C chemokine receptor type 6 (CXCR6)-VLPs CSB-MP006256HU
FADS1 Recombinant Human Fatty acid desaturase 1 (FADS1), partial CSB-MP007959HU1
LRRC8A Recombinant Human Leucine-rich repeat-containing protein 8A (LRRC8A), partial CSB-MP816895HU
RIOK2 Recombinant Human Serine/threonine-protein kinase RIO2 (RIOK2) CSB-MP887136HU
SMAD1 Recombinant Human Mothers against decapentaplegic homolog 1 (SMAD1) CSB-MP618998HU
TRIM11 Recombinant Human E3 ubiquitin-protein ligase TRIM11 (TRIM11), partial CSB-EP856931HU


參考文獻
[1] CXCR6 sustains TRM-driven psoriasis relapse by CXCL16 chemotaxis and curcumol targeting.J Adv Res,2025 Nov 01
[2]Paneth-like transition drives resistance todual targeting of KRAS and EGFR in colorectal cancer.Cancer Cell,2025 Nov 13
[3]RIOK2 kinase regulates the translocation of the FADD–RIPK1–Caspase-8 complex to the ER and the cleavage of Gasdermin D to drive pyroptosis.Nat Commun,2025 Nov 17
[4]Targeting tumor-intrinsic BCL9 reversesimmunotherapy resistance by elicitingmacrophage-mediated phagocytosis andantigen presentation.Nat Commun,2025 Nov 17
[5]FAD synthase confers ferroptosis resistance and restrains CD8+ T cell recruitment in hepatocellular carcinoma.Nat Commun,2025 Oct 29 
[6]TRIM11 potentiates antitumor immunity via blocking IFNγ/PD-L1 axis.Cell Death Differ,2025 Nov 07
[7]Endothelial LRRC8A Delays Vascular Ageing in Natural and Accelerated Ageing Mouse Models.Cardiovasc Res,2025 Dec 18
 
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