【第70期】前沿靶點(diǎn)速遞：每周醫(yī)學(xué)研究精選
日期：2026-01-07 13:58:43
01、靶點(diǎn)：SRF
應(yīng)用：防治早衰及增齡性心血管病的潛在靶點(diǎn)
來源：Vascular organoid model of Hutchinson-Gilford progeria syndrome uncovers repression of the SRF pathway in premature aging.Dev Cell,2025 Nov 27
02、靶點(diǎn)：CD2AP
應(yīng)用：HCC預(yù)后標(biāo)志物和聯(lián)合免疫-代謝治療的潛在新靶點(diǎn)
來源：CD2AP is a disulfidptosis modulator and prognostic biomarker in hepatocellular carcinoma.Clin Exp Med,2025 Nov 18
03、靶點(diǎn)：FGF4
應(yīng)用：為糖尿病腎病（DKD）提供可轉(zhuǎn)化新靶點(diǎn)
來源：FGF4-FGFR1 signaling promotes podocyte survival and glomerular function to ameliorate diabetic kidney disease in male mice.Nat Commun,2025 Nov 25
04、靶點(diǎn)：PIEZO1
應(yīng)用：為CaMKII或脂質(zhì)代謝靶向干預(yù)提供理論依據(jù)
來源：PIEZO1 gain-of-function mutation drives cardiomyopathy by disrupting myocardial lipid homeostasis besides iron overload.Sci Adv,2025 Nov 14
05、靶點(diǎn)：CTRP9
應(yīng)用：為感染與腫瘤免疫治療提供代謝干預(yù)新思路
來源：CTRP9 engages AdipoR1 and promotes T cell glycolysis and immunity.EMBO Rep,2025 Dec
06、靶點(diǎn)：HSPH1
應(yīng)用：可作為HCC預(yù)后標(biāo)志物及潛在治療靶點(diǎn)。
來源：Heat shock protein family H member 1 HSPH1 expression correlates with progression and prognosis of hepatocellular carcinoma.Sci Rep,2025 Aug 24
07、靶點(diǎn)：TRPML1/MCOLN1
應(yīng)用：為克服SHH型髓母細(xì)胞瘤通路耐藥提供新靶點(diǎn)
來源：AhR-Siglec-15 axis regulates lysosomal Ca2+ release for sonic hedgehog medulloblastoma growth via TRPML1.Protein Cell,2025 Nov 19
黃波團(tuán)隊(duì)發(fā)現(xiàn)SHH型髓母細(xì)胞瘤中，AhR受IDO1激活后轉(zhuǎn)錄上調(diào)Siglec-15，后者經(jīng)CI-MPR轉(zhuǎn)運(yùn)至溶酶體，直接激活鈣通道TRPML1→TFEB核轉(zhuǎn)位，驅(qū)動(dòng)促生長(zhǎng)基因表達(dá)，形成“AhR-Siglec-15-TRPML1-TFEB”新軸。臨床數(shù)據(jù)示Siglec-15高表達(dá)與不良預(yù)后相關(guān)，敲低或抑制該軸可顯著抑制腫瘤生長(zhǎng)，為克服SHH通路耐藥提供新靶點(diǎn)。
08、靶點(diǎn)：CISD1
應(yīng)用：為抑郁癥提供新的可靠靶點(diǎn)和干預(yù)策略
來源：Mitochondrial CISD1 Modulates Microglial Metabolic Reprogramming to Drive Stress Susceptibility in Mice.Adv Sci (Weinh),2025 Nov 11
黃松強(qiáng)團(tuán)隊(duì)發(fā)現(xiàn)慢性應(yīng)激特異性上調(diào)內(nèi)側(cè)前額葉皮層小膠質(zhì)細(xì)胞的線粒體外膜蛋白CISD1，升高NAD?/NADH比值，驅(qū)動(dòng)糖酵解代謝重編程，觸發(fā)炎癥激活并誘導(dǎo)小鼠抑郁樣行為；條件性敲除或藥理學(xué)抑制CISD1可逆轉(zhuǎn)代謝偏移、減輕神經(jīng)炎癥并改善癥狀，吡格列酮亦通過阻斷該氧化還原通路起效，為抑郁癥提供新的可靠靶點(diǎn)和干預(yù)策略。
09、靶點(diǎn)：SHMT1、PEMT
應(yīng)用：為帕金森病代謝干預(yù)提供新靶點(diǎn)與候選藥物
來源：Alternative Pathway for Methyl Supply through the Coupling of SHMT1 and PEMT to Maintain Astrocytic Homeostasis in Parkinson’s Disease.Adv Sci (Weinh),2025 Nov 20
魯明/劉陽團(tuán)隊(duì)發(fā)現(xiàn)PD患者及小鼠模型星形膠質(zhì)細(xì)胞SHMT1下調(diào)，其并非直接經(jīng)經(jīng)典一碳循環(huán)生成SAM，而是與PEMT互作，加速PC→PE轉(zhuǎn)化，間接提升SAM水平；SAM增加促進(jìn)H3K4me1修飾，上調(diào)EAAT2/GS表達(dá)，降低胞外谷氨酸，減輕興奮性毒性，保護(hù)多巴胺神經(jīng)元。虛擬篩選獲得天然化合物異葒草素，可穩(wěn)定SHMT1-PEMT復(fù)合物，增強(qiáng)該替代甲基供給通路，顯著改善PD小鼠運(yùn)動(dòng)癥狀與神經(jīng)元丟失，為帕金森病代謝干預(yù)提供新靶點(diǎn)與候選藥物。
10、靶點(diǎn)：EZH2
應(yīng)用：為靶向前列腺癌m6軸的精準(zhǔn)治療提供新策略
來源：EZH2 crosstalk with RNA methylation promotes prostate cancer progression through modulation of m6A autoregulation pathway.J Clin Invest,2025 Nov 18
11、靶點(diǎn)：GPR1/CMKLR2
應(yīng)用：為肥胖及代謝性炎癥干預(yù)提供新靶點(diǎn)與思路
來源：Noncanonical agonist-dependent and -independent arrestin recruitment of GPR1.Science,2025 Nov 20
推薦產(chǎn)品
參考文獻(xiàn)
[1]Vascular organoid model of Hutchinson-Gilford progeria syndrome uncovers repression of the SRF pathway in premature aging.Dev Cell,2025 Nov 27
[2]CD2AP is a disulfidptosis modulator and prognostic biomarker in hepatocellular carcinoma.Clin Exp Med,2025 Nov 18
[3]FGF4-FGFR1 signaling promotes podocyte survival and glomerular function to ameliorate diabetic kidney disease in male mice.Nat Commun,2025 Nov 25
[4]PIEZO1 gain-of-function mutation drives cardiomyopathy by disrupting myocardial lipid homeostasis besides iron overload.Sci Adv,2025 Nov 14
[5]CTRP9 engages AdipoR1 and promotes T cell glycolysis and immunity.EMBO Rep,2025 Dec
[6]Heat shock protein family H member 1 HSPH1 expression correlates with progression and prognosis of hepatocellular carcinoma.Sci Rep,2025 Aug 24
[7]AhR-Siglec-15 axis regulates lysosomal Ca2+ release for sonic hedgehog medulloblastoma growth via TRPML1.Protein Cell,2025 Nov 19
[8]Mitochondrial CISD1 Modulates Microglial Metabolic Reprogramming to Drive Stress Susceptibility in Mice.Adv Sci (Weinh),2025 Nov 11
[9]Alternative Pathway for Methyl Supply through the Coupling of SHMT1 and PEMT to Maintain Astrocytic Homeostasis in Parkinson’s Disease.Adv Sci (Weinh),2025 Nov 20
[10]EZH2 crosstalk with RNA methylation promotes prostate cancer progression through modulation of m6A autoregulation pathway.J Clin Invest,2025 Nov 18
[11]Noncanonical agonist-dependent and -independent arrestin recruitment of GPR1.Science,2025 Nov 20
*免責(zé)聲明：華美生物內(nèi)容團(tuán)隊(duì)僅是分享和解讀公開研究論文及其發(fā)現(xiàn)，本文僅作信息交流，文中觀點(diǎn)不代表華美生物立場(chǎng)，請(qǐng)理解。
應(yīng)用：防治早衰及增齡性心血管病的潛在靶點(diǎn)
來源：Vascular organoid model of Hutchinson-Gilford progeria syndrome uncovers repression of the SRF pathway in premature aging.Dev Cell,2025 Nov 27
圖源：10.1016/j.devcel.2025.10.019[1]
中科院劉光慧、張維綺、曲靜團(tuán)隊(duì)利用基因編輯hESC構(gòu)建哈欽森-吉爾福德早衰綜合征血管類器官，首次三維重現(xiàn)患者血管Progerin積累、核膜畸形、新生受阻等典型病變。多組學(xué)鎖定轉(zhuǎn)錄因子SRF表達(dá)下調(diào)為驅(qū)動(dòng)早衰核心事件：SRF缺失減少VEGFA通路等靶基因染色質(zhì)開放，抑制血管生成；恢復(fù)SRF可修復(fù)核形態(tài)、DNA損傷與屏障功能，并在自然衰老猴主動(dòng)脈驗(yàn)證其保守性。研究為人類血管衰老提供新模型，確立SRF為防治早衰及增齡性心血管病的潛在靶點(diǎn)。02、靶點(diǎn)：CD2AP
應(yīng)用：HCC預(yù)后標(biāo)志物和聯(lián)合免疫-代謝治療的潛在新靶點(diǎn)
來源：CD2AP is a disulfidptosis modulator and prognostic biomarker in hepatocellular carcinoma.Clin Exp Med,2025 Nov 18
圖源：10.1007/s10238-025-01917-3[2]
中山大學(xué)團(tuán)隊(duì)聯(lián)合公共數(shù)據(jù)庫多中心研究證實(shí)，支架蛋白CD2AP在HCC中顯著高表達(dá)，是不良OS/RFS的獨(dú)立預(yù)測(cè)因子。其表達(dá)與SLC7A11等二硫化物死亡基因共線，可維持肌動(dòng)蛋白骨架及NADPH穩(wěn)態(tài)，保護(hù)高SLC7A11腫瘤細(xì)胞免于葡萄糖剝奪誘導(dǎo)的二硫化物死亡；同時(shí)CD2AP抑制CD8+T細(xì)胞浸潤(rùn)并上調(diào)PD-L1等免疫檢查點(diǎn)，降低ICB療效。敲低CD2AP可在體外顯著抑制增殖、遷移并增敏代謝應(yīng)激死亡，提示其可作為HCC預(yù)后標(biāo)志物和聯(lián)合免疫-代謝治療的潛在新靶點(diǎn)。03、靶點(diǎn)：FGF4
應(yīng)用：為糖尿病腎病（DKD）提供可轉(zhuǎn)化新靶點(diǎn)
來源：FGF4-FGFR1 signaling promotes podocyte survival and glomerular function to ameliorate diabetic kidney disease in male mice.Nat Commun,2025 Nov 25
圖源：10.1038/s41467-025-65978-4[3]
溫州醫(yī)科大學(xué)黃志鋒/周潔/孫健團(tuán)隊(duì)發(fā)現(xiàn)，足細(xì)胞分泌的FGF4在糖尿病腎?。―KD）中顯著下降，其水平與疾病嚴(yán)重程度負(fù)相關(guān)。足細(xì)胞特異性缺失FGF4加速腎損傷，而外源重組FGF4通過激活FGFR1-AMPK-FOXO1軸增強(qiáng)抗氧化、抑制凋亡，恢復(fù)足細(xì)胞穩(wěn)態(tài)并改善腎功能，在人類足細(xì)胞與腎組織亦顯效，為DKD提供可轉(zhuǎn)化新靶點(diǎn)。04、靶點(diǎn)：PIEZO1
應(yīng)用：為CaMKII或脂質(zhì)代謝靶向干預(yù)提供理論依據(jù)
來源：PIEZO1 gain-of-function mutation drives cardiomyopathy by disrupting myocardial lipid homeostasis besides iron overload.Sci Adv,2025 Nov 14
圖源：10.1126/sciadv.ady9242[4]
山東大學(xué)陳玉國(guó)、徐峰、崔素梅團(tuán)隊(duì)發(fā)現(xiàn)，PIEZO1功能獲得突變（D669Y/D674Y）通過持續(xù)升高心肌細(xì)胞內(nèi)Ca²?，激活CaMKII，磷酸化下調(diào)FOXO3，抑制脂質(zhì)分解與線粒體脂肪酸氧化，誘發(fā)脂毒性；同時(shí)突變亦致鐵攝入通道轉(zhuǎn)錄上調(diào)、鐵沉積，但單細(xì)胞測(cè)序與突變小鼠證明心功能不全主要由脂質(zhì)穩(wěn)態(tài)破壞驅(qū)動(dòng)，鐵超載僅起協(xié)同作用。該發(fā)現(xiàn)首次揭示PIEZO1-Ca²?-CaMKII-FOXO3軸為擴(kuò)張型心肌病新機(jī)制，支持將其納入臨床遺傳篩查，并為CaMKII或脂質(zhì)代謝靶向干預(yù)提供理論依據(jù)。05、靶點(diǎn)：CTRP9
應(yīng)用：為感染與腫瘤免疫治療提供代謝干預(yù)新思路
來源：CTRP9 engages AdipoR1 and promotes T cell glycolysis and immunity.EMBO Rep,2025 Dec
圖源：10.1038/s44319-025-00640-0[5]
華東師大楊嘉龍團(tuán)隊(duì)發(fā)現(xiàn)，脂肪因子CTRP9通過AdipoR1觸發(fā)Ca²?-CaM-CaMKKβ-AMPK軸，增強(qiáng)T細(xì)胞糖酵解、增殖與效應(yīng)功能；而經(jīng)典配體ADPN則抑制糖酵解，從而解釋AdipoR1對(duì)免疫的雙向調(diào)控。該機(jī)制在羅非魚和小鼠中保守，且CTRP9可提升CAR-T抗淋巴瘤活性，為感染與腫瘤免疫治療提供代謝干預(yù)新思路。06、靶點(diǎn)：HSPH1
應(yīng)用：可作為HCC預(yù)后標(biāo)志物及潛在治療靶點(diǎn)。
來源：Heat shock protein family H member 1 HSPH1 expression correlates with progression and prognosis of hepatocellular carcinoma.Sci Rep,2025 Aug 24
圖源：10.1038/s41598-025-16843-3[6]
綜合TCGA、GEO數(shù)據(jù)庫及85例臨床HCC樣本分析顯示，熱休克蛋白HSPH1在癌組織與四種HCC細(xì)胞系中顯著高表達(dá)，且與晚期TNM分期、低分化及高AFP水平相關(guān)。Kaplan-Meier與多因素Cox證實(shí)HSPH1高表達(dá)為獨(dú)立不良預(yù)后因素（HR=1.70，P=0.02）。功能上，敲低HSPH1抑制Huh7/Hep3B增殖和集落形成；GSEA提示其富集于細(xì)胞周期、DNA復(fù)制及p53通路，并驅(qū)動(dòng)M0/M1巨噬細(xì)胞浸潤(rùn)、抑制Treg與活化NK，塑造促瘤免疫微環(huán)境。HSPH1可作為HCC預(yù)后標(biāo)志物及潛在治療靶點(diǎn)。07、靶點(diǎn)：TRPML1/MCOLN1
應(yīng)用：為克服SHH型髓母細(xì)胞瘤通路耐藥提供新靶點(diǎn)
來源：AhR-Siglec-15 axis regulates lysosomal Ca2+ release for sonic hedgehog medulloblastoma growth via TRPML1.Protein Cell,2025 Nov 19
圖源：10.1093/procel/pwaf100[7]
黃波團(tuán)隊(duì)發(fā)現(xiàn)SHH型髓母細(xì)胞瘤中，AhR受IDO1激活后轉(zhuǎn)錄上調(diào)Siglec-15，后者經(jīng)CI-MPR轉(zhuǎn)運(yùn)至溶酶體，直接激活鈣通道TRPML1→TFEB核轉(zhuǎn)位，驅(qū)動(dòng)促生長(zhǎng)基因表達(dá)，形成“AhR-Siglec-15-TRPML1-TFEB”新軸。臨床數(shù)據(jù)示Siglec-15高表達(dá)與不良預(yù)后相關(guān)，敲低或抑制該軸可顯著抑制腫瘤生長(zhǎng)，為克服SHH通路耐藥提供新靶點(diǎn)。
08、靶點(diǎn)：CISD1
應(yīng)用：為抑郁癥提供新的可靠靶點(diǎn)和干預(yù)策略
來源：Mitochondrial CISD1 Modulates Microglial Metabolic Reprogramming to Drive Stress Susceptibility in Mice.Adv Sci (Weinh),2025 Nov 11
圖源：10.1002/advs.202508957[8]
黃松強(qiáng)團(tuán)隊(duì)發(fā)現(xiàn)慢性應(yīng)激特異性上調(diào)內(nèi)側(cè)前額葉皮層小膠質(zhì)細(xì)胞的線粒體外膜蛋白CISD1，升高NAD?/NADH比值，驅(qū)動(dòng)糖酵解代謝重編程，觸發(fā)炎癥激活并誘導(dǎo)小鼠抑郁樣行為；條件性敲除或藥理學(xué)抑制CISD1可逆轉(zhuǎn)代謝偏移、減輕神經(jīng)炎癥并改善癥狀，吡格列酮亦通過阻斷該氧化還原通路起效，為抑郁癥提供新的可靠靶點(diǎn)和干預(yù)策略。
09、靶點(diǎn)：SHMT1、PEMT
應(yīng)用：為帕金森病代謝干預(yù)提供新靶點(diǎn)與候選藥物
來源：Alternative Pathway for Methyl Supply through the Coupling of SHMT1 and PEMT to Maintain Astrocytic Homeostasis in Parkinson’s Disease.Adv Sci (Weinh),2025 Nov 20
圖源：10.1002/advs.202516794[9]
魯明/劉陽團(tuán)隊(duì)發(fā)現(xiàn)PD患者及小鼠模型星形膠質(zhì)細(xì)胞SHMT1下調(diào)，其并非直接經(jīng)經(jīng)典一碳循環(huán)生成SAM，而是與PEMT互作，加速PC→PE轉(zhuǎn)化，間接提升SAM水平；SAM增加促進(jìn)H3K4me1修飾，上調(diào)EAAT2/GS表達(dá)，降低胞外谷氨酸，減輕興奮性毒性，保護(hù)多巴胺神經(jīng)元。虛擬篩選獲得天然化合物異葒草素，可穩(wěn)定SHMT1-PEMT復(fù)合物，增強(qiáng)該替代甲基供給通路，顯著改善PD小鼠運(yùn)動(dòng)癥狀與神經(jīng)元丟失，為帕金森病代謝干預(yù)提供新靶點(diǎn)與候選藥物。
10、靶點(diǎn)：EZH2
應(yīng)用：為靶向前列腺癌m6軸的精準(zhǔn)治療提供新策略
來源：EZH2 crosstalk with RNA methylation promotes prostate cancer progression through modulation of m6A autoregulation pathway.J Clin Invest,2025 Nov 18
圖源：10.1172/JCI195840[10]
易旸/曹圻/楊仁東團(tuán)隊(duì)發(fā)現(xiàn)EZH2通過酶活依賴途徑驅(qū)動(dòng)前列腺癌m6A自我增強(qiáng)回路：EZH2甲基化并穩(wěn)定FOXA1→轉(zhuǎn)錄上調(diào)m6A閱讀器YTHDF1→增強(qiáng)METTL14/WTAP翻譯→提升整體m6A水平，加速細(xì)胞周期等關(guān)鍵mRNA翻譯，促進(jìn)腫瘤生長(zhǎng)。聯(lián)合EZH2 PROTAC降解劑MS8815與m6A抑制劑STM2457在細(xì)胞和PDX模型中協(xié)同抑制腫瘤，為靶向EZH2-m6A軸的精準(zhǔn)治療提供新策略。11、靶點(diǎn)：GPR1/CMKLR2
應(yīng)用：為肥胖及代謝性炎癥干預(yù)提供新靶點(diǎn)與思路
來源：Noncanonical agonist-dependent and -independent arrestin recruitment of GPR1.Science,2025 Nov 20
圖源：10.1126/science.adt8794[11]
上海藥物所吳蓓麗等聯(lián)合團(tuán)隊(duì)解析GPR1與趨化素及β-arrestin1/2復(fù)合物的高分辨率結(jié)構(gòu)，首次揭示無配體狀態(tài)下GPR1仍可招募β-arrestin1的“清道夫”模式，闡明其通過阻遏蛋白偏向信號(hào)和脂質(zhì)輔助內(nèi)吞精細(xì)調(diào)控趨化素穩(wěn)態(tài)，并與CMKLR1協(xié)作影響脂質(zhì)代謝，為肥胖及代謝性炎癥干預(yù)提供新靶點(diǎn)與思路。推薦產(chǎn)品
| 靶點(diǎn) | 重組蛋白 | 貨號(hào) |
| CD2AP | Recombinant Human CD2-associated protein (CD2AP) | CSB-MP004914HU |
| CISD1 | Recombinant Human CDGSH iron-sulfur domain-containing protein 1 (CISD1), partial | CSB-MP868365HU |
| CMKLR2 | Recombinant Rat Chemerin-like receptor 2 (Cmklr2) | CSB-CF009728RA |
| EZH2 | Recombinant Human Histone-lysine N-methyltransferase EZH2 (EZH2) | CSB-YP613606HU |
| FGF4 | Recombinant Human Fibroblast growth factor 4 (FGF4), partial (Active) | CSB-AP003981HU |
| HSPH1 | Recombinant Human Heat shock protein 105 kDa (HSPH1), partial | CSB-MP852885HU |
| MCOLN1 | Recombinant Human Mucolipin-1 (MCOLN1) | CSB-CF872417HU |
| PEMT | Recombinant Human Phosphatidylethanolamine N-methyltransferase (PEMT), partial | CSB-MP017780HU1 |
| PIEZO1 | Recombinant Human Piezo-type mechanosensitive ion channel component 1 (PIEZO1), partial | CSB-EP852881HU |
| SHMT1 | Recombinant Human Serine hydroxymethyltransferase, cytosolic (SHMT1) | CSB-MP021272HU |
| SRF | Recombinant Human Serum response factor (SRF) | CSB-YP022659HU |
參考文獻(xiàn)
[1]Vascular organoid model of Hutchinson-Gilford progeria syndrome uncovers repression of the SRF pathway in premature aging.Dev Cell,2025 Nov 27
[2]CD2AP is a disulfidptosis modulator and prognostic biomarker in hepatocellular carcinoma.Clin Exp Med,2025 Nov 18
[3]FGF4-FGFR1 signaling promotes podocyte survival and glomerular function to ameliorate diabetic kidney disease in male mice.Nat Commun,2025 Nov 25
[4]PIEZO1 gain-of-function mutation drives cardiomyopathy by disrupting myocardial lipid homeostasis besides iron overload.Sci Adv,2025 Nov 14
[5]CTRP9 engages AdipoR1 and promotes T cell glycolysis and immunity.EMBO Rep,2025 Dec
[6]Heat shock protein family H member 1 HSPH1 expression correlates with progression and prognosis of hepatocellular carcinoma.Sci Rep,2025 Aug 24
[7]AhR-Siglec-15 axis regulates lysosomal Ca2+ release for sonic hedgehog medulloblastoma growth via TRPML1.Protein Cell,2025 Nov 19
[8]Mitochondrial CISD1 Modulates Microglial Metabolic Reprogramming to Drive Stress Susceptibility in Mice.Adv Sci (Weinh),2025 Nov 11
[9]Alternative Pathway for Methyl Supply through the Coupling of SHMT1 and PEMT to Maintain Astrocytic Homeostasis in Parkinson’s Disease.Adv Sci (Weinh),2025 Nov 20
[10]EZH2 crosstalk with RNA methylation promotes prostate cancer progression through modulation of m6A autoregulation pathway.J Clin Invest,2025 Nov 18
[11]Noncanonical agonist-dependent and -independent arrestin recruitment of GPR1.Science,2025 Nov 20
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