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淫羊藿苷（ICA）是一种源自淫羊藿属植物的异戊二烯基黄酮类化合物，近年来在肝细胞癌（HCC）治疗中受到关注。研究显示，ICA具有多靶点协同抗肿瘤作用，可通过诱导细胞衰老、细胞凋亡和铁死亡/铁自噬等构建抗HCC综合作用网络。ICA可激活活性氧介导的DNA损伤反应及p53/p21信号轴，并抑制糖酵解代谢重编程，诱导肿瘤细胞衰老。同时，ICA可通过调控Bcl-2/Bax平衡、激活caspase级联反应并下调甲胎蛋白表达，协同促进肿瘤细胞凋亡。此外，ICA还可通过干扰抗氧化体系、调节铁稳态并激活铁自噬，增强肿瘤细胞对脂质过氧化损伤的敏感性，诱导铁死亡，从而强化其抗肿瘤效应。此外，临床试验结果显示，ICA可延长晚期HCC患者的中位总生存期且安全性良好，在联合免疫治疗及靶向治疗中也有潜在应用价值。但其具体分子机制、优势人群筛选及药物递送技术仍有待深入研究。总体而言，ICA作为一种多靶点天然小分子，在HCC 治疗中具有良好的应用前景和临床转化价值。
Abstract：Icariin (ICA)， a prenylated flavonoid derived from Epimedium species， has recently attracted attention for its therapeutic potential in hepatocellular carcinoma (HCC). Accumulating evidence indicates that ICA exerts multitarget and synergistic antitumor effects by orchestrating multiple cell death programs， including cellular senescence， apoptosis， and ferroptosis/ferritinophagy， thereby forming an integrated anti-HCC regulatory network. Mechanistically， ICA induces tumor cell senescence by activating reactive oxygen species-mediated DNA damage responses and the p53/p21 signaling axis， while concurrently suppressing glycolytic metabolic reprogramming. In parallel， ICA promotes apoptosis through modulation of the Bcl-2/Bax balance， activation of the caspase cascade， and downregulation of alpha-fetoprotein expression. Furthermore， ICA enhances ferroptosis by disrupting antioxidant defense systems， regulating iron homeostasis， and activating ferritinophagy， thereby increasing tumor cell susceptibility to lipid peroxidation–induced damage. Clinical studies have demonstrated that ICA can prolong the median overall survival of patients with advanced HCC with a favorable safety profile， and it also shows potential in combination with immunotherapy and targeted therapy. However， its precise molecular mechanisms， optimal patient selection strategies， and drug delivery systems require further investigation. Overall， ICA， as a multitarget natural small molecule， exhibits promising therapeutic potential and translational value in the treatment of HCC.
[1] UDOMSINPRASERT W， SOBHONSLIDSUK A， JITTIKOON J， et al. Cellular senescence in liver fibrosis: implications for age-related chronic liver diseases[J]. Expert Opin Ther Targets， 2021，25(9):799-813.
[2] ZHANG S， ZHENG Y， LI X， et al. Cellular senescence-related gene signature as a valuable predictor of prognosis in hepatocellular carcinoma[J]. Aging (Albany NY)， 2023，15(8):3064-3093...
[3] ZHANG C， SUI X， JIANG Y， et al. Antitumor effects of icaritin and the molecular mechanisms[J]. Discov Med， 2020，29(156):5-16.
[4] CORREIA-MELO C， MARQUES F D M， ANDERSON R， et al. Mitochondria are required for pro-ageing features of the senescent phenotype[J]. EMBO J， 2016，35(7):724-742.
[5] KUDRYAVTSEVA A V， KRASNOV G S， DMITRIEV A A， et al. Mitochondrial dysfunction and oxidative stress in aging and cancer[J]. Oncotarget， 2016，7(29):44879-44905.
[6] WANG S， WANG Q， WANG H， et al. Induction of ROS and DNA damage-dependent senescence by icaritin contributes to its antitumor activity in hepatocellular carcinoma cells[J]. Pharm Biol， 2019，57(1):424-431.
[7] ZHENG X， GOU Y， JIANG Z， et al. Icaritin-induced FAM99A affects GLUT1-mediated glycolysis via regulating the JAK2/STAT3 pathway in HCC cells[J]. Front Oncol， 2021，11:740557.
[8] SHANG RZ， QU SB， WANG DS. Reprogramming of glucose metabolism in hepatocellular carcinoma: progress and prospects[J]. World J Gastroenterol， 2016，22(45):9933-9943.
[9] LI S H， HAO L Y， HU X Y. Natural products target glycolysis in liver disease[J]. Front Pharmacol， 2023，14:1108052.
[10] ZHOU X， WU D， MI T， et al. Icaritin activates p53 and inhibits aerobic glycolysis in liver cancer cells[J]. Chem Biol Interact， 2024，392:110926.
[11] JIAO Y Y， LI W Q， YANG W， et al. Icaritin exerts anti-cancer effects through modulating pyroptosis and immune activities in hepatocellular carcinoma[J]. Biomedicines， 2024，12(8):1917.
[12] TAO H M， LIU M Y， WANG Y， et al. Icaritin induces anti-tumor immune responses in hepatocellular carcinoma by inhibiting splenic myeloid-derived suppressor cell generation[J]. Front Immunol， 2021，12:609295.
[13] LU Y， LUO Q， JIA X， et al. Nanomedicine-boosting icaritin-based immunotherapy of advanced hepatocellular carcinoma[J]. Mil Med Res， 2022，9(1):69.
[14] ELMORE S. Apoptosis: a review of programmed cell death[J]. Toxicol Pathol， 2007，35(4):495-516.
[15] RIEDL S J， SALVESEN G S. The apoptosome: signalling platform of cell death[J]. Nat Rev Mol Cell Biol， 2007，8(5):405-413.
[16] SUN L， CHEN W， QU L， et al. Anticancer agent icaritin induces apoptosis through caspase-dependent pathways in human hepatocellular carcinoma cells[J]. Mol Med Rep， 2015，11(4):3094-3100.
[17] YU Z， GUO J F， HU M Y， et al. Icaritin exacerbates mitophagy and synergizes with doxorubicin to induce immunogenic cell death in hepatocellular carcinoma[J]. ACS Nano， 2020，14(4):4816-4828.
[18] WANG Z D， WANG R Z， XIA Y Z， et al. Reversal of multidrug resistance by icaritin in doxorubicin-resistant human osteosarcoma cells[J]. Chin J Nat Med， 2018，16(1):20-28.
[19] SHI A， SHEN T， XIA W， et al. Icaritin enhances sorafenib-induced apoptosis through a mitochondria-dependent pathway[J]. J Chin Pharm Sci， 2022，31(12):928-937.
[20] DAVIS R J. Signal transduction by the JNK group of MAP kinases[J]. Cell， 2000，103(2):239-252.
[21] HE J， WANG Y， DUAN F， et al. Icaritin induces apoptosis of HepG2 cells via the JNK1 signaling pathway independent of the estrogen receptor[J]. Planta Med， 2010，76:1834-1839.
[22] LU P H， CHEN M B， LIU Y Y， et al. Identification of sphingosine kinase 1 (SphK1) as a primary target of icaritin in hepatocellular carcinoma cells[J]. Oncotarget， 2017，8:22800-22810.
[23] TONG J S， ZHANG Q H， HUANG X， et al. Icaritin causes sustained ERK1/2 activation and induces apoptosis in human endometrial cancer cells[J]. PLoS One， 2011，6:e16781.
[24] LI H， SUN L， PENG Q， et al. Icaritin promotes apoptosis and inhibits proliferation by down-regulating AFP through MDM2/p53 pathways in hepatocellular carcinoma cells[J]. BMC Cancer， 2021，21(1):318.
[25] LEE K C， CROWE A J， BARTON M C. p53-mediated repression of alpha-fetoprotein gene expression by specific DNA binding[J]. Mol Cell Biol， 1999，19(2):1279-1288.
[26] OGDEN S K， LEE K C， WERNKE-DOLLRIES K， et al. p53 represses hepatic AFP gene expression by direct interaction with an HNF-3/p53 composite element[J]. J Biol Chem， 2001，276(42):39246-39254.
[27] W?LFEL G， OSTHEIM E， STAUB A， et al. The p53 family of transcription factors represses the alpha-fetoprotein gene expression in hepatocellular carcinoma[J]. J Gastrointestin Liver Dis， 2023，32(3):346-355.
[28] YU J， ZHANG L， HWANG PM， et al. PUMA induces the rapid apoptosis of colorectal cancer cells[J]. Mol Cell， 2001，7(3):673-682.
[29] KOCEMBA-PILARCZYK K A， OSTROWSKA B， TROJAN S E， et al. Deciphering enemy tactics—the narrow path to an optimal anti-cancer strategy targeting the Warburg effect[J]. Pharmacol Rep， 2025，77(5):1143-1162.
[30] ZHAO H， WANG J， FANG D， et al. A novel anti-cancer agent icaritin suppresses hepatocellular carcinoma tumor-initiating cells and STAT3 signaling[J]. Oncotarget， 2015，6(32):31918-31933.
[31] JIANG Y， YU Y， PAN Z， et al. Ferroptosis: a new hunter of hepatocellular carcinoma[J]. Cell Death Discov， 2024，10(1):136.
[32] TANG X， ZHANG C， HUANG J， et al. The synergy of gene targeting drug icaritin soft capsule with immunomodulator and TACE brings new hope for drug combination in patients with advanced liver cancer: a case report and literature review[J]. Cancer Management and Research， 2023，15:707-717.
[33] LUO P， ZHANG H， CHEN J Q， et al. Antineoplastic effects of icaritin: molecular mechanisms and applications[J]. Acta Mater Med， 2025，4(2):186-199.
[34] ZHU X Y， SHA X D， ZANG Y， et al. Current progress of ferroptosis study in hepatocellular carcinoma[J]. Int J Biol Sci， 2024，20(9):3621-3638.
[35] GUO R， YAN Z， WANG R， et al. Advances in pharmacological research on icaritin: a comprehensive review[J]. Am J Chin Med， 2025，53(1):179-203.
[36] HSIEH C H. Selective autophagy in hepatocellular carcinoma[J]. Exp Ther Med， 2025， 30(1):37.
[37] HAN L Y， Tian X M， Yang X X， et al. The pathogenesis of hepatocellular carcinoma: ERK/ULK1/NCOA4-mediated inhibition of iron autophagy， and Epimedium extract targeted modulation of this pathway to treat hepatocellular carcinoma[J]. Phytomedicine， 2025， 141:156666.
[38] LUO P， AN Y， HE J， et al. Icaritin with autophagy/mitophagy inhibitors synergistically enhances anticancer efficacy and apoptotic effects through PINK1/Parkin-mediated mitophagy in hepatocellular carcinoma[J]. Cancer Lett， 2024，587:216621.
[39] CHEN S， SUN Y， XIE Y， et al. Mitochondria-targeted icaritin nanoparticles induce immunogenic cell death in hepatocellular carcinoma[J]. ACS Appl Mater Interfaces， 2025，17(2):2899-2910. .
[40] SUN Y， QIN S， LI W， et al. A randomized， double-blinded， phase III study of icaritin versus huachashu as the first-line therapy in biomarker-enriched HBV-related advanced hepatocellular carcinoma with poor conditions: Interim analysis result[J]. J Clin Oncol， 2021，39(S15): 4077.
[41] WANG Y， ZHU H， et al. Nanomedicine for the delivery of icaritin: enhancing its anticancer effect and overcoming pharmacokinetic challenges[J]. J Drug Target， 2025，32(5):486-496.
基本信息:
中图分类号:R285
引用信息:
[1]刘要男,颉佳丽,赵睿.淫羊藿苷通过诱导细胞衰老、凋亡和铁死亡抗肝细胞癌的机制研究进展[J].山东医药().
基金信息:
国家自然科学基金项目（32060230）; 甘肃省自然科学基金项目（20JR10RA718）
2026-03-30
2026-03-30
2026-03-30