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【第77期】前沿靶點速遞:每周醫學研究精選

日期:2026-03-10 11:05:55


01、靶點:IFI16
應用:復制應激相關癌癥的潛在治療靶點
來源:IFI16 senses and protects stalled replication forks.Mol Cell,2026 Jan 2
 
圖源:10.1016/j.molcel.2025.12.024[1]
 
英國Staples與Unterholzner團隊在Molecular Cell發文,揭示先天免疫傳感器IFI16在復制應激中扮演“感知-保護”雙重角色:它直接結合停滯復制叉的新生DNA,阻止MRE11等核酸酶降解,維持基因組穩定;同時通過cGAS-STING非經典途徑激活NF-κB,迅速誘導炎癥因子表達。IFI16缺失既加劇復制叉崩潰,又削弱BRCA1/2缺陷細胞對干擾素的挽救效應,提示其橋聯DNA損傷應答與先天免疫。該發現為復制應激相關癌癥治療提供新靶點。


02、靶點:CMKLR1
應用:男性生殖衰老的潛在治療靶點
來源:Targeting the CMKLR1-Mediated Signaling Rebalances Immunometabolism State in Middle-Age Testicular Macrophages.Adv Sci (Weinh),2026 Jan 15
 
圖源:10.1002/advs.202515166[2]

中科院深圳先進院張鍵團隊發現,中年肥胖時脂肪因子Chemerin經CMKLR1受體激活睪丸駐留巨噬細胞,使其轉向促炎糖酵解表型,破壞免疫穩態并加速精子發生衰退;該機制在人鼠保守。敲除Cmklr1、拮抗肽P12C5或高強度間歇運動均可抑制CMKLR1信號,重塑巨噬細胞代謝與M2極化,恢復睪丸抗炎微環境,從而延緩性腺衰老。研究提出“脂肪–Chemerin–CMKLR1–睪丸巨噬細胞”軸是男性生殖衰老可干預的新靶點。


03、靶點:ADAM12
應用:結直腸癌的潛在治療靶點
來源:Single-cell screens identify ADAM12 as a fibroblast checkpoint impeding anti-tumor immunity.Cancer Cell,2026 Feb 09
 
 
圖源:10.1016/j.ccell.2025.12.018[3]

北大BIOPIC張澤民、席建忠團隊聯合構建結直腸癌患者原代成纖維細胞庫,整合計算預測與CRISPRi/a Perturb-seq功能篩選,鎖定CAFs關鍵檢查點ADAM12。敲除或抑制ADAM12可阻斷TGFβ信號、激活I型干擾素反應,使促瘤肌成纖維細胞轉為抗瘤表型,疏松基質并增強CD8?T細胞浸潤,在B16、MC38、KPC、LLC模型中顯著抑瘤,且與PD-L1阻斷協同克服“冷腫瘤”耐藥。公共數據亦證實ADAM12高表達與低免疫浸潤及不良預后正相關,為安全精準的微環境靶向免疫聯合治療提供新策略。


04、靶點:RAD21L1
應用:非梗阻性無精子癥的治療
來源:RAD21L1 Is Sufficient and Effective for Reprogramming Human Sertoli Cells to Phenotypic Spermatogonial Stem Cells Through DNA Methylation and Essential for Male Fertility.Adv Sci (Weinh),2025 Dec
 
圖源:10.1002/advs.202417491[4]

海南醫科大學何祖平團隊發現,單基因RAD21L1可通過上調DNMT1介導DNA甲基化,將人支持細胞高效、安全地重編程為具有減數分裂潛能的精原干細胞,效率優于傳統DAZ三基因方案;且在1455例非梗阻性無精子癥(NOA)患者中,RAD21L1罕見突變占比2.8%,顯著增加生精失敗風險。研究揭示了一條從體細胞獲取男性配子的新途徑,為NOA患者提供無需自身精子即可產生遺傳學后代的可能,并確立RAD21L1作為不育遺傳診斷和再生干預的雙重新靶點。


05、靶點:KLHL6
應用:T細胞耗竭的治療
來源:The Ubiquitin Ligase KLHL6 Drives Resistance to CD8+ T Cell Dysfunction.Nature,2026 Jan 14
 
圖源:10.1038/s41586-025-09926-8[5]

中國醫學科學院李貴登與Fred Hutchinson中心Philip Greenberg團隊合作,在Nature報道E3泛素連接酶KLHL6是CD8?T細胞耗竭與線粒體損傷的雙重負向調控因子:KLHL6催化TOX降解抑制終末耗竭,并通過PGAM5-Drp1軸阻止過度線粒體分裂;慢性TCR信號經FOXO1下調KLHL6,導致功能喪失。過繼T細胞中增強KLHL6表達可顯著提升抗腫瘤及抗病毒效力,為突破CAR-T/TCR-T耗竭瓶頸提供可臨床轉化的多功能新靶點。


06、靶點: MAT2A
應用:糖尿病傷口愈合的治療
來源:A biomimetic senotherapy replenishing MAT2A promotes wound regeneration in preclinical models.Nat Commun,2025 Nov 26
 
圖源:10.1038/s41467-025-65659-2[6]

中山大學唐冰等團隊在Nature Communications發現:糖尿病傷口周細胞中蛋氨酸腺苷轉移酶MAT2A下調→通過OTUB1-HMGCS1-CoQ軸破壞線粒體穩態→誘導衰老并分泌SASP因子、向巨噬細胞轉移線粒體→驅動M1極化與慢性炎癥。團隊構建周細胞膜包裹的MAT2A自擴增RNA納米顆粒,可恢復CoQ合成、逆轉衰老、減少促炎巨噬浸潤,顯著加速糖尿病小鼠創面愈合且安全,為慢性炎癥相關損傷提供可轉化“代謝-衰老-免疫”干預新策略。


07、靶點:TRPM4
應用:治療包括神經源性腸功能障礙等多種病因引起的便秘
來源:Noncanonical calcium-independent TRPM4 activation governs intestinal fluid homeostasis.Nat Commun,2026 Jan 08
 
圖源:10.1038/s41467-025-68014-7[7]

中美團隊發現,60年經典瀉藥比沙可啶的活性代謝物去乙酰比沙可啶(DAB)通過靶向腸上皮TRPM4通道的全新非鈣依賴口袋,選擇性激活鈉內流→鈣通道-NCX-鈣內流→ANO1氯通道→水分泌通路,像“總閥門”一樣調節腸道水分。基因敲除TRPM4后DAB完全失效,證實其必需地位;該口袋與心臟等組織鈣結合位點分離,為設計精準激活或抑制TRPM4的便秘/腹瀉新藥奠定基礎,并提示TRPM4在心血管等系統具更廣藥物開發潛力。


08、靶點:ACLY、ACSS2
應用:代謝相關脂肪性肝炎(MASH)及肝纖維化的治療
來源:Dual inhibition of ACLY and ACSS2 by EVT0185
reduces steatosis, hepatic stellate cell activation, and fibrosis in mouse models of MASH.Cell Metab,2026 Jan 06
 
圖源:10.1016/j.cmet.2025.11.015[8]

《細胞-代謝》新研究指出,MASH患者肝內乙酰輔酶A生成酶ACLY與ACSS2表達升高,驅動脂肪新生和膽固醇合成,進而活化肝星狀細胞(HSCs)促纖維化。雙重抑制劑EVT0185可同時阻斷ACLY/ACSS2,抑制乙酸-ACSS2-膽固醇通路,在體外和人肝切片中減少脂滴沉積,阻斷TGF-β1誘導的HSC活化,并在動物模型中顯著減輕脂肪變性、胰島素抵抗及肝纖維化。空間轉錄組與單細胞測序證實其主要通過ACSS2調控乙酸鹽代謝和膽固醇合成,為MASH和纖維化治療提供“雙靶點、雙代謝”新策略。


推薦產品

靶點 重組蛋白 貨號
ADAR Recombinant Human Double-stranded RNA-specific adenosine deaminase (ADAR), partial CSB-MP001324HU
ALDH1L1 Recombinant Human Cytosolic 10-formyltetrahydrofolate dehydrogenase (ALDH1L1), partial CSB-MP001569HU
CASTOR1 Recombinant Human Cytosolic arginine sensor for mTORC1 subunit 1 (CASTOR1) CSB-MP848815HU
CASTOR2 Recombinant Human Cytosolic arginine sensor for mTORC1 subunit 2 (CASTOR2) CSB-YP2823HU
HDAC1 Recombinant Human Histone deacetylase 1 (HDAC1) CSB-EP010235HU
HLTF Recombinant Human Helicase-like transcription factor (HLTF), partial CSB-MP010520HU
IL17REL Recombinant Human Putative interleukin-17 receptor E-like (IL17REL) CSB-MP754581HU
LAMP1 Recombinant Human Lysosome-associated membrane glycoprotein 1 (LAMP1), partial (Active) CSB-AP005091HU
NLRP6 Recombinant Human NACHT, LRR and PYD domains-containing protein 6 (NLRP6) CSB-BP015874HU(A4)
PDCD5 Recombinant Human Programmed cell death protein 5 (PDCD5) CSB-EP017671HU
SIRT3 Recombinant Human NAD-dependent protein deacetylase sirtuin-3, mitochondrial (SIRT3), partial CSB-EP882102HU1
 
 
參考文獻

[1]IFI16 senses and protects stalled replication forks.Mol Cell,2026 Jan 2
[2]Targeting the CMKLR1-Mediated Signaling Rebalances Immunometabolism State in Middle-Age Testicular Macrophages.Adv Sci (Weinh),2026 Jan 15
[3]Single-cell screens identify ADAM12 as a fibroblast checkpoint impeding anti-tumor immunity.Cancer Cell,2026 Feb 09
[4]RAD21L1 Is Sufficient and Effective for Reprogramming Human Sertoli Cells to Phenotypic Spermatogonial Stem Cells Through DNA Methylation and Essential for Male Fertility.Adv Sci (Weinh),2025 Dec
[5]The Ubiquitin Ligase KLHL6 Drives Resistance to CD8+ T Cell Dysfunction.Nature,2026 Jan 14
[6]A biomimetic senotherapy replenishing MAT2A promotes wound regeneration in preclinical models.Nat Commun,2025 Nov 26
[7]Noncanonical calcium-independent TRPM4 activation governs intestinal fluid homeostasis.Nat Commun,2026 Jan 08
[8]Dual inhibition of ACLY and ACSS2 by EVT0185 reduces steatosis, hepatic stellate cell activation, and fibrosis in mouse models of MASH.Cell Metab,2026 Jan 06
 
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