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A novel photosensitizer berberine derivative B12 induces apoptosis and suppresses HIF-1α expression in colorectal cancer cells via mitochondria-to-nucleus sequential-targeting

Acta Pharmacologica Sinica volume 47, pages 1249–1269 (2026) Cite this article

Abstract

Photodynamic therapy (PDT) boasts the advantages of high spatiotemporal selectivity and non-invasiveness, but its clinical application is still limited by the hypoxic tumor microenvironment and inherent drawbacks of traditional photosensitizers such as aggregation-induced quenching (ACQ), insufficient targeting ability, and systemic toxicity. We previously conducted a structure-activity relationship (SAR) study on a plant-derived alkaloid, berberine, and found that its derivative B12 not only significantly enhanced antitumor efficacy but also improved water solubility and bioavailability. In this study, we characterized the photodynamic properties of B12, investigated its anticancer mechanisms, and evaluated the photodynamic therapeutic efficacy and biosafety of B12 in the tumors of xenograft mouse models. We showed that B12 was a novel photosensitizer without ACQ effect, exhibited both type I and type II photodynamic activities, and generated a large amount of reactive oxygen species (ROS) under both normoxic and hypoxic conditions. In addition, B12 (12.5, 25 μM) significantly enhanced its therapeutic effect against RKO and HCT116 cells in the hypoxic microenvironment by inhibiting the AKT/mTOR signaling pathway and downregulating the expression of hypoxia-inducible factor HIF-1α. In RKO cells, B12 (2 μM) exhibited dynamic dual-organelle-targeting properties after photoactivation: it first induced the collapse of mitochondrial membrane potential, then translocated to the nucleus and bound to DNA. It improved the intersystem crossing (ISC) efficiency by narrowing the singlet-triplet energy gap, thereby amplifying the generation of ROS and damaging DNA integrity. In mice xenografted with B16 cells, intratumoral injection of B12 (5 mg/kg) followed by 10 min light irradiation daily for 9 days significantly suppressed tumor growth with good biosafety. In conclusion, the small molecule B12 simultaneously possesses type I and type II photodynamic activities, dynamic organelle-targeting and hypoxia adaptation properties. This study may provide a reference for the research and design of hypoxia-tolerant small-molecule photosensitizers and break through the clinical bottlenecks of photodynamic therapy.

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Fig. 1: Optical properties and ROS generation of B12.
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Fig. 2: Type I photodynamic effects of B12 in RKO cells.
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Fig. 3: Evaluation of the tumor selectivity of B12.
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Fig. 4: B12 targeted mitochondria and migrated to the nucleus after light activation.
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Fig. 5: B12-induced apoptosis by impaired MMP.
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Fig. 6: B12 bound to DNA and induced DNA cleavage by light activation.
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Fig. 7: B12 alleviated intracellular hypoxia.
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Fig. 8: B12 alleviated intracellular hypoxia and induced ICD.
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Fig. 9: B12 restrained tumor growth in vivo.
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Fig. 10: Schematic diagram.
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References

  1. Rodrigues JA, Correia JH. Enhanced photodynamic therapy: a review of combined energy sources. Cells. 2022;11:3995.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Overchuk M, Weersink RA, Wilson BC, Zheng G. Photodynamic and photothermal therapies: synergy opportunities for nanomedicine. ACS Nano. 2023;17:7979–8003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Luo H, Gao S. Recent advances in fluorescence imaging-guided photothermal therapy and photodynamic therapy for cancer: from near-infrared-I to near-infrared-II. J Control Release. 2023;362:425–45.

    Article  CAS  PubMed  Google Scholar 

  4. Yu Y, Wu S, Zhang L, Xu S, Dai C, Gan S, et al. Cationization to boost both type I and type II ROS generation for photodynamic therapy. Biomaterials. 2022;280:121255.

    Article  CAS  PubMed  Google Scholar 

  5. Larue L, Myrzakhmetov B, Ben-Mihoub A, Moussaron A, Thomas N, Arnoux P, et al. Fighting hypoxia to improve PDT. Pharmaceuticals. 2019;12:163.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Sun Y, Zhou Z, Yang S, Yang H. Modulating hypoxia inducible factor-1 by nanomaterials for effective cancer therapy. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2022;14:e1766.

    Article  CAS  PubMed  Google Scholar 

  7. Liu P, Xie X, Shi X, Peng Y, Ding J, Zhou W. Oxygen-self-supplying and HIF-1alpha-inhibiting core-shell nanosystem for hypoxia-resistant photodynamic therapy. ACS Appl Mater Interfaces. 2019;11:48261–70.

    Article  CAS  PubMed  Google Scholar 

  8. Park JM, Hong KI, Lee H, Jang WD. Bioinspired applications of porphyrin derivatives. Acc Chem Res. 2021;54:2249–60.

    Article  CAS  PubMed  Google Scholar 

  9. Yuan G, Lv C, Liang J, Zhong X, Li Y, He J, et al. Molecular engineering of efficient singlet oxygen generators with near-infrared AIE features for mitochondrial targeted photodynamic therapy. Adv Funct Mater. 2021;31:2104026.

    Article  CAS  Google Scholar 

  10. Hu F, Xu S, Liu B. Photosensitizers with aggregation-Induced emission: materials and biomedical applications. Adv Mater. 2018;30:e1801350.

    Article  PubMed  Google Scholar 

  11. Zhao H, Xu J, Feng C, Ren J, Bao L, Zhao Y, et al. Tailoring aggregation extent of photosensitizers to boost phototherapy potency for eliciting systemic antitumor immunity. Adv Mater. 2022;34:e2106390.

    Article  PubMed  Google Scholar 

  12. Yu G, Yu S, Saha ML, Zhou J, Cook TR, Yung BC, et al. A discrete organoplatinum(II) metallacage as a multimodality theranostic platform for cancer photochemotherapy. Nat Commun. 2018;9:4335.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Yu Y, Xiang L, Zhang X, Zhang L, Ni Z, Zhu ZH, et al. Pure organic AIE nanoscintillator for X-ray mediated type I and type II photodynamic therapy. Adv Sci. 2023;10:e2302395.

    Article  Google Scholar 

  14. Battogtokh G, Choi YS, Kang DS, Park SJ, Shim MS, Huh KM, et al. Mitochondria-targeting drug conjugates for cytotoxic, anti-oxidizing and sensing purposes: current strategies and future perspectives. Acta Pharm Sin B. 2018;8:862–80.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Feng Q, Xu J, Zhuang C, Xiong J, Wang H, Xiao K. Mitochondria-targeting and multiresponsive nanoplatform based on AIEgens for synergistic chemo-photodynamic therapy and enhanced immunotherapy. Biomacromolecules. 2023;24:977–90.

    Article  CAS  PubMed  Google Scholar 

  16. Dong Y, Fan H, Zhang Z, Jiang F, Li M, Zhou H, et al. Berberine ameliorates DSS-induced intestinal mucosal barrier dysfunction through microbiota-dependence and Wnt/β-catenin pathway. Int J Biol Sci. 2022;18:1381–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yang L, Zhu W, Zhang X, Zhou X, Wu W, Shen T. Efficacy and safety of berberine for several cardiovascular diseases: a systematic review and meta-analysis of randomized controlled trials. Phytomedicine. 2023;112:154716.

    Article  CAS  PubMed  Google Scholar 

  18. Cui G, Wang H, Yang C, Zhou X, Wang J, Wang T, et al. Berberine prevents lethal EV71 neurological infection in newborn mice. Front Pharmacol. 2022;13:1027566.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Liu L, Fan J, Ai G, Liu J, Luo N, Li C, et al. Berberine in combination with cisplatin induces necroptosis and apoptosis in ovarian cancer cells. Biol Res. 2019;52:37.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Brezová V, Dvoranová D, Kost'álová D. Oxygen activation by photoexcited protoberberinium alkaloids from Mahonia aquifolium. Phytother Res. 2004;18:640–6.

    Article  PubMed  Google Scholar 

  21. Lee MMS, Zheng L, Yu B, Xu W, Kwok RTK, Lam JWY, et al. A highly efficient and AIE-active theranostic agent from natural herbs. Mater Chem Front. 2019;3:1454–61.

    Article  CAS  Google Scholar 

  22. Pan Y, Shao D, Zhao Y, Zhang F, Zheng X, Tan Y, et al. Berberine reverses hypoxia-induced chemoresistance in breast cancer through the inhibition of AMPK- HIF-1α. Int J Biol Sci. 2017;13:794–803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. An YW, Jin HT, Yuan B, Wang JC, Wang C, Liu HQ. Research progress of berberine mediated photodynamic therapy. Oncol Lett. 2021;21:359.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Görner H, Miskolczy Z, Megyesi M, Biczók L. Photoreduction and ketone-sensitized reduction of alkaloids. Photochem Photobiol. 2011;87:284–91.

    Article  PubMed  Google Scholar 

  25. Xu B, Jiang X, Xiong J, Lan J, Tian Y, Zhong L, et al. Structure-activity relationship study enables the discovery of a novel berberine analogue as the RXRalpha activator to inhibit colon cancer. J Med Chem. 2020;63:5841–55.

    Article  CAS  PubMed  Google Scholar 

  26. Kang M, Zhou C, Wu S, Yu B, Zhang Z, Song N, et al. Evaluation of structure-function relationships of aggregation-Induced emission luminogens for simultaneous dual applications of specific discrimination and efficient photodynamic killing of gram-positive bacteria. J Am Chem Soc. 2019;141:16781–9.

    Article  CAS  PubMed  Google Scholar 

  27. Lee HR, Leslie F, Azarin SM. A facile in vitro platform to study cancer cell dormancy under hypoxic microenvironments using CoCl2. J Biol Eng. 2018;12:12.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Lee HR, Pelaez F, Silbaugh AM, Leslie F, Racila E, Azarin SM. Biomaterial platform to establish a hypoxic metastatic niche in vivo. ACS Appl Bio Mater. 2019;2:1549–60.

    Article  CAS  PubMed  Google Scholar 

  29. Li Y, Hu D, Pan M, Qu Y, Chu B, Liao J, et al. Near-infrared light and redox dual-activatable nanosystems for synergistically cascaded cancer phototherapy with reduced skin photosensitization. Biomaterials. 2022;288:121700.

    Article  CAS  PubMed  Google Scholar 

  30. Kang M, Zhang Z, Xu W, Wen H, Zhu W, Wu Q, et al. Good steel used in the blade: well-tailored type-I photosensitizers with aggregation-induced emission characteristics for precise nuclear targeting photodynamic therapy. Adv Sci. 2021;8:e2100524.

    Article  Google Scholar 

  31. Zielonka J, Joseph J, Sikora A, Hardy M, Ouari O, Vasquez-Vivar J, et al. Mitochondria-targeted triphenylphosphonium-based compounds: syntheses, mechanisms of action, and therapeutic and diagnostic applications. Chem Rev. 2017;117:10043–120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hirakawa K, Hirano T. The microenvironment of DNA switches the activity of singlet oxygen generation photosensitized by berberine and palmatine. Photochem Photobiol. 2008;84:202–8.

    Article  CAS  PubMed  Google Scholar 

  33. Xi W, Yu J, Wei M, Qiu Q, Xu P, Qian Z, et al. Photophysical switching between aggregation-induced phosphorescence and dual-state emission by isomeric substitution. Chemistry. 2020;26:3733–7.

    Article  CAS  PubMed  Google Scholar 

  34. Sun Y, Zhao D, Wang G, Wang Y, Cao L, Sun J, et al. Recent progress of hypoxia-modulated multifunctional nanomedicines to enhance photodynamic therapy: opportunities, challenges, and future development. Acta Pharm Sin B. 2020;10:1382–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Mao QY, Wang XQ, Lin F, Yu MW, Fan HT, Zheng Q, et al. Scorpiones, scolopendra and gekko inhibit lung cancer growth and metastasis by ameliorating hypoxic tumor microenvironment via PI3K/AKT/mTOR/HIF-1α signaling pathway. Chin J Integr Med. 2024;30:799–808.

    Article  CAS  PubMed  Google Scholar 

  36. Weng ML, Chen WK, Chen XY, Lu H, Sun ZR, Yu Q, et al. Fasting inhibits aerobic glycolysis and proliferation in colorectal cancer via the Fdft1-mediated AKT/mTOR/HIF1α pathway suppression. Nat Commun. 2020;11:1869.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhao ZX, Li S, Liu LX. Thymoquinone affects hypoxia-inducible factor-1α expression in pancreatic cancer cells via HSP90 and PI3K/AKT/mTOR pathways. World J Gastroenterol. 2024;30:2793–816.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Li Z, Lai X, Fu S, Ren L, Cai H, Zhang H, et al. Immunogenic cell death activates the tumor immune microenvironment to boost the immunotherapy efficiency. Adv Sci. 2022;9:e2201734.

    Article  Google Scholar 

  39. Xu B, Luo X, Xiong J, Shen Q, Su Y, Lei Z, et al. Berplatin: a conjugate of berberine and cisplatin serving as a potent antitumor agent with distinctive tumor cell uptake and minimal side effects. Adv Ther. 2022;6:2200160.

    Article  Google Scholar 

  40. Zhang C, Xia D, Liu J, Huo D, Jiang X, Hu Y. Bypassing the immunosuppression of myeloid-derived suppressor cells by reversing tumor hypoxia using a platelet-inspired platform. Adv Funct Mater. 2020;30:2000189.

    Article  CAS  Google Scholar 

  41. Zhou S, Jiang L, Li C, Mao H, Jiang C, Wang Z, et al. Acid and hypoxia tandem-activatable deep near-infrared nanoprobe for two-step signal amplification and early detection of cancer. Adv Mater. 2023;35:e2212231.

    Article  PubMed  Google Scholar 

  42. Ge L, Qiao C, Tang Y, Zhang X, Jiang X. Light-activated hypoxia-sensitive covalent organic framework for tandem-responsive drug delivery. Nano Lett. 2021;21:3218–24.

    Article  CAS  PubMed  Google Scholar 

  43. Wicks EE, Semenza GL. Hypoxia-inducible factors: cancer progression and clinical translation. J Clin Invest. 2022;132:e159839.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Shi Y, Gilkes DM. HIF-1 and HIF-2 in cancer: structure, regulation, and therapeutic prospects. Cell Mol Life Sci. 2025;82:44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Stegeman H, Span PN, Kaanders JH, Bussink J. Improving chemoradiation efficacy by PI3-K/AKT inhibition. Cancer Treat Rev. 2014;40:1182–91.

    Article  CAS  PubMed  Google Scholar 

  46. Wan Y, Fu LH, Li C, Lin J, Huang P. Conquering the hypoxia limitation for photodynamic therapy. Adv Mater. 2021;33:e2103978.

    Article  PubMed  Google Scholar 

  47. Chen K, Zhai Y, Wang Y, Xu Z, Chen X, Zhang Y, et al. H2O2 promotes photodynamic efficacy of TMPyP4 against ovarian cancer in vitro by downregulating HIF-1α expression. Biomed Pharmacother. 2024;177:117110.

    Article  CAS  PubMed  Google Scholar 

  48. Li M, Xiong J, Zhang Y, Yu L, Yue L, Yoon C, et al. New guidelines and definitions for type I photodynamic therapy. Chem Soc Rev. 2025;54:7025–57.

    Article  CAS  PubMed  Google Scholar 

  49. Zhan Q, Kuang Y, Chen X, Yang Y, Jiang L, Chen J, et al. Photo-generating type-I ROS and aryl radicals by mitochondrial-targeting oxime-ester photogenerator for pyroptosis-mediated anti-hypoxia photoimmunotherapy. Bioact Mater. 2025;47:327–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Wang H, Qin T, Wang W, Zhou X, Lin F, Liang G, et al. Selenium-containing type-I organic photosensitizers with dual reactive oxygen species of superoxide and hydroxyl radicals as switch-hitter for photodynamic therapy. Adv Sci. 2023;10:e2301902.

    Article  Google Scholar 

  51. Wang YY, Liu YC, Sun H, Guo DS. Type I photodynamic therapy by organic–inorganic hybrid materials: from strategies to applications. Coord Chem Rev. 2019;395:46–62.

    Article  CAS  Google Scholar 

  52. Chen D, Xu Q, Wang W, Shao J, Huang W, Dong X. Type I photosensitizers revitalizing photodynamic oncotherapy. Small. 2021;17:2006742.

    Article  CAS  Google Scholar 

  53. Zeng Q, Ma X, Song Y, Chen Q, Jiao Q, Zhou L. Targeting regulated cell death in tumor nanomedicines. Theranostics. 2022;12:817–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Wang R, Li X, Yoon J. Organelle-targeted photosensitizers for precision photodynamic therapy. ACS Appl Mater Interfaces. 2021;13:19543–71.

    Article  CAS  PubMed  Google Scholar 

  55. Tian H, Zhu N, Wang H, Li Y, Yang Q, Chen H, et al. Self-oxygenated hydrogel enhances immune cell response and infiltration via triggering dual DNA damage to activate cGAS-STING and inhibiting CAFs. Small. 2024;20:e2403428.

    Article  PubMed  Google Scholar 

  56. Mai Y, Liu X, Fang Z, Peng Y, Hu L, Wu Z, et al. An AIE-active type I/II photosensitizer with mitochondria-to-nuclei cascade targeting for highly efficient photodynamic cancer therapy. Mater Today Bio. 2025;34:102134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wang KN, Liu LY, Qi G, Chao XJ, Ma W, Yu Z, et al. Light-driven cascade mitochondria-to-nucleus photosensitization in cancer cell ablation. Adv Sci. 2021;8:2004379.

    Article  CAS  Google Scholar 

  58. Guo L, Cao X, Li X, Xu J, Zhao X, Lu H. Nucleus and mitochondria double-targeted phototherapeutic agent based on conjugated small molecule for cancer cell-targeted synergistic phototherapy. Sens Actuators B Chem. 2024;418:136227.

    Article  CAS  Google Scholar 

  59. Li YH, Jia HR, Wang HY, Hua XW, Bao YW, Wu FG. Mitochondrion, lysosome, and endoplasmic reticulum: which is the best target for phototherapy?. J Control Release. 2022;351:692–702.

    Article  CAS  PubMed  Google Scholar 

  60. Xu X, Li Z, Zhao J, Liu Y, Xu Y, Jia Y, et al. Catalase-conjugated rose bengal biological nanoparticles with mitochondrial selectivity toward photodynamic therapy. CCS Chem. 2023;5:2877–87.

    Article  CAS  Google Scholar 

  61. Pereira GC, Branco AF, Matos JA, Pereira SL, Parke D, Perkins EL, et al. Mitochondrially targeted effects of berberine [natural yellow 18, 5,6-dihydro-9,10-dimethoxybenzo(g)-1,3-benzodioxolo(5,6-a) quinolizinium] on K1735-M2 mouse melanoma cells: comparison with direct effects on isolated mitochondrial fractions. J Pharmacol Exp Ther. 2007;323:636–49.

    Article  CAS  PubMed  Google Scholar 

  62. Lyamzaev KG, Pustovidko AV, Simonyan RA, Rokitskaya TI, Domnina LV, Ivanova OY, et al. Novel mitochondria-targeted antioxidants: plastoquinone conjugated with cationic plant alkaloids berberine and palmatine. Pharm Res. 2011;28:2883–95.

    Article  CAS  PubMed  Google Scholar 

  63. Li Q, Zhou T, Liu C, Wang XY, Zhang JQ, Wu F, et al. Mitochondrial membrane potential played crucial roles in the accumulation of berberine in HepG2 cells. Biosci Rep. 2019;39:BSR20190477.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Tuo J, Xie Y, Song J, Chen Y, Guo Q, Liu X, et al. Development of a novel berberine-mediated mitochondria-targeting nano-platform for drug-resistant cancer therapy. J Mater Chem B. 2016;4:6856–64.

    Article  CAS  PubMed  Google Scholar 

  65. Li X, Wang Z, Hao X, Zhang J, Zhao X, Yao Y, et al. Optically pure double-stranded dinuclear Ir(III) metallohelices enabled chirality-induced photodynamic responses. J Am Chem Soc. 2023;145:14766–75.

    Article  CAS  PubMed  Google Scholar 

  66. Levental I, Lyman E. Regulation of membrane protein structure and function by their lipid nano-environment. Nat Rev Mol Cell Biol. 2023;24:107–22.

    Article  CAS  PubMed  Google Scholar 

  67. Chen L, Si W, Zhang L, Tang G, Li ZT, Hou JL. Chiral selective transmembrane transport of amino acids through artificial channels. J Am Chem Soc. 2013;135:2152–5.

    Article  CAS  PubMed  Google Scholar 

  68. Wen W, Li J, Shang W, Zhuang Z, Deng X, Yan X, et al. Dual-organelle targeted photosensitizer with AIE characteristics for triple-negative breast cancer photodynamic therapy via apoptosis and immunogenic cell death. Mater Today Bio. 2025;32:101828.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Luo T, Fan Y, Mao J, Jiang X, Albano L, Yuan E, et al. Metal-organic layer delivers 5-aminolevulinic acid and porphyrin for dual-organelle-targeted photodynamic therapy. Angew Chem Int Ed. 2023;62:e202301910.

    Article  CAS  Google Scholar 

  70. Yang J, Ren B, Yin X, Xiang L, Hua Y, Huang X, et al. Expanded ROS generation and hypoxia reversal: excipient-free self-assembled nanotheranostics for enhanced cancer photodynamic immunotherapy. Adv Mater. 2024;36:e2402720.

    Article  PubMed  Google Scholar 

  71. Li W, Yang J, Luo L, Jiang M, Qin B, Yin H, et al. Targeting photodynamic and photothermal therapy to the endoplasmic reticulum enhances immunogenic cancer cell death. Nat Commun. 2019;10:3349.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Guo Z, Liu Y, Chen D, Sun Y, Li D, Meng Y, et al. Targeting regulated cell death: apoptosis, necroptosis, pyroptosis, ferroptosis, and cuproptosis in anticancer immunity. J Transl Int Med. 2025;13:10–32.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Gao W, Wang X, Zhou Y, Wang X, Yu Y. Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy. Signal Transduct Target Ther. 2022;7:196.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Huang C, Lin B, Chen C, Wang H, Lin X, Liu J, et al. Synergistic reinforcing of immunogenic cell death and transforming tumor-associated aacrophages via a multifunctional cascade bioreactor for optimizing cancer immunotherapy. Adv Mater. 2022;34:e2207593.

    Article  PubMed  Google Scholar 

  75. Zhang W, Chen G, Chen Z, Yang X, Zhang B, Wang S, et al. Mitochondria-targeted polyprodrug nanoparticles induce mitochondrial stress for immunogenic chemo-photodynamic therapy of ovarian cancer. J Control Release. 2024;371:470–83.

    Article  CAS  PubMed  Google Scholar 

  76. Yin M, Dong J, Sun C, Liu X, Liu Z, Liu L, et al. Raddeanin a enhances mitochondrial DNA-cGAS/STING axis-mediated antitumor immunity by targeting transactive responsive DNA-binding protein 43. Adv Sci. 2023;10:e2206737.

    Article  Google Scholar 

  77. Mianowska M, Zaremba-Czogalla M, Zygmunt A, Mahmud M, Süss R, Gubernator J. Dual role of vitamin C-encapsulated liposomal berberine in effective colon anticancer immunotherapy. Pharmaceuticals. 2023;17:5.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Liu Y, Liu X, Zhang N, Yin M, Dong J, Zeng Q, et al. Berberine diminishes cancer cell PD-L1 expression and facilitates antitumor immunity via inhibiting the deubiquitination activity of CSN5. Acta Pharm Sin B. 2020;10:2299–312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Shah D, Challagundla N, Dave V, Patidar A, Saha B, Nivsarkar M, et al. Berberine mediates tumor cell death by skewing tumor-associated immunosuppressive macrophages to inflammatory macrophages. Phytomedicine. 2022;99:153904.

    Article  CAS  PubMed  Google Scholar 

  80. Hu J, Shi Q, Xue C, Wang Q. Berberine protects against hepatocellular carcinoma progression by regulating intrahepatic T cell heterogeneity. Adv Sci. 2024;11:e2405182.

    Article  Google Scholar 

  81. Shurin MR, Umansky V. Cross-talk between HIF and PD-1/PD-L1 pathways in carcinogenesis and therapy. J Clin Invest. 2022;132:e159473.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Ding XC, Wang LL, Zhang XD, Xu JL, Li PF, Liang H, et al. The relationship between expression of PD-L1 and HIF-1α in glioma cells under hypoxia. J Hematol Oncol. 2021;14:92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (82204424, 82472651, 22471227, 22071205), Open Research Project of the Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases (Ministry of Education), Gannan Medical University (XN202005), the Scientific Research Foundation of State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory (2023XAKJ0101005), and Shenzhen Science and Technology Program (JCYJ20210324121802008, JCYJ20220530143406015).

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Author notes

  1. These authors contributed equally: Wen-bin Pei, Zi-yu Lei, Fu-quan Xie

Authors and Affiliations

  1. Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen, 361102, China

    Wen-bin Pei, Zi-yu Lei, Yong-cheng Su, Jiang-quan Li, Qian-wen Shen, Miao-miao Ma, Chun-yi Gao, Jia-chen Zhu, Ya-jie Xu, Kai-yue Zhang, Wen-qing Zhang & Tian-hui Hu

  2. Cancer Hospital, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, China

    Zi-yu Lei, Yong-cheng Su & Tian-hui Hu

  3. Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases (Ministry of Education), Gannan Medical University, Ganzhou, 341000, China

    Zi-yu Lei & Tian-hui Hu

  4. Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Third Military Medical University (Army Medical University), Chongqing, 400037, China

    Fu-quan Xie

  5. Chongqing Key Laboratory of Precision Medicine and Prevention of Major Respiratory Diseases, Chongqing, 400037, China

    Fu-quan Xie

  6. Department of Chemistry and Key Laboratory of Chemical Biology of Fujian Province, iChEM, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China

    Peng Chen, Yu-shan Qin & Yan-dong Zhang

  7. Shenzhen Research Institute of Xiamen University, Shenzhen, 518057, China

    Tian-hui Hu

  8. Department of Stem Cell and Regenerative Medicine, International Joint Research Center for Precision Biotherapy, Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China

    Bei-bei Xu

  9. Jin-feng Laboratory, Chongqing, 401329, China

    Bei-bei Xu

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Contributions

WBP, ZYL, and FQX performed the experiments and drafted the manuscript. PC, YCS, YSQ, JQL, QWS, MMM, CYG, JCZ, KYZ, YJX, and WQZ performed part of the experiments. WBP, ZYL, FQX, YDZ, THH, and BBX conceived the hypothesis and designed the experiments. WBP, FQX, THH, YDZ, and BBX revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Yan-dong Zhang, Tian-hui Hu or Bei-bei Xu.

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Pei, Wb., Lei, Zy., Xie, Fq. et al. A novel photosensitizer berberine derivative B12 induces apoptosis and suppresses HIF-1α expression in colorectal cancer cells via mitochondria-to-nucleus sequential-targeting. Acta Pharmacol Sin 47, 1249–1269 (2026). https://doi.org/10.1038/s41401-025-01728-y

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