Citation: Xiaoqin Pan, Changsheng Li, Xinyi Ai, Changqing Tao, Jingchuan He, Tingting Li, Zhihua Deng, Xiaocheng Mo, Ya Chen, Xiumei Qin, Dongmei Wang, Ronghua Jin, Jie Yang. Targeted delivery of nitidine chloride inducing ferroptosis and necroptosis as a novel anti-lung squamous cell carcinoma strategy[J]. Chinese Chemical Letters, ;2026, 37(6): 111968. doi: 10.1016/j.cclet.2025.111968 shu

Targeted delivery of nitidine chloride inducing ferroptosis and necroptosis as a novel anti-lung squamous cell carcinoma strategy

Xiaoqin Pan ^{a, b, 1} ,
Changsheng Li ^{a, 1} ,
Xinyi Ai ^{a, 1} ,
Changqing Tao ^c ,
Jingchuan He ^{a, d} ,
Tingting Li ^{a, e} ,
Zhihua Deng ^{a, f} ,
Xiaocheng Mo ^g ,
Ya Chen ^a ,
Xiumei Qin ^a ,
Dongmei Wang ^{h, *,} ,
Ronghua Jin ^{a, *,} ,
Jie Yang ^{a, i, j, *,}

a.
Department of Pharmacology, School of Pharmacy, Guangxi Medical University, Nanning 530021, China
b.
Department of Pharmacy, the First Affiliated Hospital of Guangxi University of Science and technology, Liuzhou 545000, China
c.
Department of Traditional Chinese Medicine, School of the First Clinical Medical College, Guangxi Medical University, Nanning 530021, China
d.
Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning 530021, China
e.
Department of Pharmacy, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, China
f.
Department of Gastrointestinal Medicine, Affiliated Hospital of YouJiang Medical University for Nationalities, Baise 533000, China
g.
Department of Pharmacy, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
h.
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
i.
Guangxi Key Laboratory of Drug Basic Research for Prevention and Treatment of Geriatric Diseases, School of Pharmacy, Guangxi Medical University, Nanning 530021, China
j.
The Laboratory of Toxicology of Traditional Chinese Medicine, Level Ⅲ Laboratory of National Administration of Traditional Chinese Medicine, School of Pharmacy, Guangxi Medical University, Nanning 530021, China

wangdmchina@imm.ac.cn

jinronghua@gxmu.edu.cn

jieyang2016@gxmu.edu.cn

Received Date: 16 August 2025
Revised Date: 12 October 2025
Accepted Date: 14 October 2025
Available Online: 15 October 2025

Figures(6)

Nitidine chloride (NC) exhibits potent antitumor activity through ferroptosis induction. However, its clinical application is limited by poor aqueous solubility and non-selective cytotoxicity. To overcome these challenges, we developed a pH-responsive delivery system (HD@NC@MOF), combining a hyaluronic acid (HA)-cloaked and mixed-valence iron-based metal-organic framework (Fe-MOF), enabling strategic targeting of lung squamous cell carcinoma (LUSC) cells via CD44 receptor recognition. Within the acidic intracellular microenvironment, HD@NC@MOF co-releases NC and iron ions, triggering a profound reactive oxygen species (ROS) surge, and ultimately inducing ferroptosis and necroptosis through the solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) and receptor-interacting serine/threonine-protein kinase 1 (RIPK1)/receptor-interacting serine/threonine-protein kinase 3 (RIPK3)/mixed lineage kinase domain-like protein (MLKL) pathways. In vitro, HD@NC@MOF exhibited significantly enhanced selective cytotoxicity towards LUSC cells compared to free NC (selectivity index improved from 0.54 to 2.58). Mechanistic studies revealed that NC stimulated mitochondrial ROS production, synergizing with Fe-MOF-derived iron to amplify oxidative stress. In vivo, HD@NC@MOF achieved a 69.02% tumor inhibition rate (1.72-fold higher than free NC) with minimal systemic toxicity. This work highlighted the potential of HD@NC@MOF as an efficient and targeted carrier for NC in LUSC chemotherapy.
- Nitidine chloride,
- Mixed-valence metal-organic frameworks,
- Necroptosis,
- Ferroptosis,
- Lung squamous cell carcinoma
1. [1]
  F. Bray, M. Laversanne, H. Sung, et al., CA Cancer J. Clin. 74 (2024) 229–263. doi: 10.3322/caac.21834
2. [2]
  H. Sung, J. Ferlay, R.L. Siegel, et al., CA Cancer J. Clin. 71 (2021) 209–249. doi: 10.3322/caac.21660
3. [3]
  Y. Shen, J.Q. Chen, X.P. Li, Genes Dis. 12 (2025) 101374. doi: 10.1016/j.gendis.2024.101374
4. [4]
  Z.Z. Wang, H. Tang, Acad. J. Naval Med. Univ. 46 (2025) 17–23.
5. [5]
  N. Vasan, J. Baselga, D.M. Hyman, Nature 575 (2019) 299–309. doi: 10.1038/s41586-019-1730-1
6. [6]
  S.Y. Sun, Cancer Lett. 604 (2024) 217203. doi: 10.1016/j.canlet.2024.217203
7. [7]
  Y. Yang, B. Jiang, L. Shi, et al., J. Ethnopharmacol. 346 (2025) 119555. doi: 10.1016/j.jep.2025.119555
8. [8]
  H. Zheng, Y. Chen, W. Luo, et al., J. Nanobiotechnol. 23 (2025) 357. doi: 10.1186/s12951-025-03378-y
9. [9]
  C.L. Yao, J.Q. Zhang, J.Y. Li, et al., Nat. Prod. Rep. 38 (2021) 1618–1633. doi: 10.1039/d0np00057d
10. [10]
  D.J. Newman, G.M. Cragg, J. Nat. Prod. 79 (2016) 629–661. doi: 10.1021/acs.jnatprod.5b01055
11. [11]
  F. Yu, W. Tan, Z. Chen, et al., Chin. Med. 17 (2022) 115. doi: 10.1186/s13020-022-00671-y
12. [12]
  F. Yu, Z. Luo, L. Li, et al., Chin. Pharmacol. Bull. 38 (2022) 1023–1031.
13. [13]
  Y. Lin, K.F. Qiu, F.C. Qin, et al., Chin. J. Mod. Appl. Pharm. 29 (2012) 1032–1034.
14. [14]
  F.H. Luo, Z.H. Chen, F.F. Zeng, et al., J. Ethnopharmacol. 337 (2025) 118783. doi: 10.1016/j.jep.2024.118783
15. [15]
  Y.W. Chen, G.H. Liu, L. Yang, et al., Lishizhen Med. Mater. Med. Res. 21 (2010) 1121–1122.
16. [16]
  Q. Lu, S. Luo, Z. Shi, et al., Front. Pharmacol. 13 (2022) 1046402. doi: 10.3389/fphar.2022.1046402
17. [17]
  J. Bouquet, M. Rivaud, S. Chevalley, E. Deharo, V. Jullian, A. Valentin, Malar. J. 11 (2012) 67. doi: 10.1186/1475-2875-11-67
18. [18]
  D.M. Anwar, M. El-Sayed, A. Reda, et al., Expert Opin. Drug Deliv. 18 (2021) 1609–1625. doi: 10.1080/17425247.2021.1955853
19. [19]
  J. He, T. Li, X. Pan, et al., Biomaterials 323 (2025) 123407. doi: 10.1016/j.biomaterials.2025.123407
20. [20]
  T. Briolay, T. Petithomme, M. Fouet, et al., Mol. Cancer 20 (2021) 55.
21. [21]
  Z. Liu, S. Liu, B. Liu, et al., Chin. Chem. Lett. 35 (2024) 109626. doi: 10.1016/j.cclet.2024.109626
22. [22]
  B. Niu, K. Liao, Y. Zhou, et al., Biomaterials 277 (2021) 121110.
23. [23]
  X. Zhao, S. He, B. Li, et al., Nano Lett. 23 (2023) 863–871. doi: 10.1021/acs.nanolett.2c04042
24. [24]
  M. Parsaei, K. Akhbari, Inorg. Chem. 61 (2022) 19354–19368. doi: 10.1021/acs.inorgchem.2c03138
25. [25]
  G. Lin, J. Chen, X. Liu, et al., Chin. Chem. Lett. 36 (2025) 111018. doi: 10.1016/j.cclet.2025.111018
26. [26]
  C. Yao, J. Tian, H. Wang, et al., Chin. Chem. Lett. 28 (2017) 893–899. doi: 10.1016/j.cclet.2017.01.005
27. [27]
  Z. Yin, Y. Lv, L. Deng, et al., Free Radic. Biol. Med. 203 (2023) 86–101. doi: 10.1016/j.freeradbiomed.2023.04.003
28. [28]
  J. Lu, Y. Li, X. Qin, et al., J. Colloid Interface Sci. 702 (2026) 138849. doi: 10.1016/j.jcis.2025.138849
29. [29]
  Y.H. Ko, H.S. Won, E.K. Jeon, et al., BMC Cancer 11 (2011) 340. doi: 10.1186/1471-2407-11-340
30. [30]
  H. Xu, M. Niu, X. Yuan, et al., Exp. Hematol. Oncol. 9 (2020) 36.
31. [31]
  J. Chandra, N. Molugulu, S. Annadurai, et al., Environ. Res. 233 (2023) 116506.
32. [32]
  A. Mansouri, N.K. Farsani, A. Javanmard, et al., Int. J. Biol. Macromol. 308 (2025) 142253.
33. [33]
  X. Li, F. Xiong, X. Cao, et al., Chin. Chem. Lett. 37 (2026) 110970. doi: 10.1016/j.cclet.2025.110970
34. [34]
  Y. Zhang, S.S. Su, S. Zhao, et al., Nat. Commun. 8 (2017) 14329.
35. [35]
  Z. Su, Z. Yang, Y. Xu, et al., Mol. Cancer 14 (2015) 48.
36. [36]
  A. Ambujakshan, B.D. Sahu, Biochem. Pharmacol. 231 (2025) 116642.
37. [37]
  R. Yuan, W. Zhao, Q. -Q. Wang, et al., Pharmacol. Res. 170 (2021) 105748.
38. [38]
  N. Wang, Y. Liu, D. Peng, et al., Adv. Healthc. Mater. 13 (2024) e2401646.
39. [39]
  B. Perillo, M. Di Donato, A. Pezone, et al., Exp. Mol. Med. 52 (2020) 192–203. doi: 10.1038/s12276-020-0384-2
40. [40]
  Y. Gao, P. Wang, Y. Chu, et al., Water Res. 248 (2024) 120826.
41. [41]
  H.J. Kwon, L.H. Kim, C.H. Ahn, et al., J. Clin. Biochem. Nutr. 65 (2019) 193–202. doi: 10.3164/jcbn.19-28
42. [42]
  J. Dan Dunn, L.A. Alvarez, X. Zhang, et al., Redox Biol. 6 (2015) 472–485.
43. [43]
  W.D. Cook, D.M. Moujalled, T.J. Ralph, et al., Cell Death Differ. 21 (2014) 1600–1612. doi: 10.1038/cdd.2014.70
44. [44]
  Z. Ding, R. Wang, Y. Li, X. Wang, Mol. Cell 85 (2025) 2610–2625. e5.
45. [45]
  Y. Hong, W.Q. Xu, J. Feng, et al., Acta Pharmacol. Sin. 44 (2023) 561–572. doi: 10.1038/s41401-022-00968-6
46. [46]
  D. Li, S. Liu, J. Zhu, et al., BMC Pharmacol. Toxicol. 22 (2021) 1.
47. [47]
  J. Bi, Y. Zheng, L. Fang, et al., Organomet. Polym. Mater. 30 (2020) 3388–3395. doi: 10.1007/s10904-020-01548-z
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2. [2]
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3. [3]
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4. [4]
  Yongzhi Wu , Rong He , Bowen Tan , Longjiang Li , Jinfeng Liao . An injectable hydrogel for chemodynamic therapy-induced ferroptosis in malignant melanoma. Chinese Chemical Letters, 2026, 37(3): 111339-. doi: 10.1016/j.cclet.2025.111339
5. [5]
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6. [6]
  Zhendong Liu , Sainan Liu , Bin Liu , Qi Meng , Meng Yuan , Chunzheng Yang , Yulong Bian , Ping'an Ma , Jun Lin . Fe(Ⅲ)-juglone nanoscale coordination polymers for cascade chemodynamic therapy through synergistic ferroptosis and apoptosis strategy. Chinese Chemical Letters, 2024, 35(11): 109626-. doi: 10.1016/j.cclet.2024.109626
7. [7]
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8. [8]
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9. [9]
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10. [10]
  Mengyu Cao , Yiyan Yin , Jingyi Qin , Jin Ouyang , Na Na . Unconventional application of a fluorescent probe for MS-based detection of multiple sulfur species in ferroptosis. Chinese Chemical Letters, 2026, 37(1): 111260-. doi: 10.1016/j.cclet.2025.111260
11. [11]
  Yaheng Li , Weijiang He , Yuncong Chen , Zijian Guo . A BODIPY-based ratiometric fluorescent probe for imaging of Zn²⁺ in ferroptosis. Chinese Chemical Letters, 2026, 37(5): 111337-. doi: 10.1016/j.cclet.2025.111337
12. [12]
  Guanghui Lin , Jieyao Chen , Xiaojia Liu , Yitong Lin , Xudong Zhu , Guotao Yuan , Bowen Yang , Shuanshuan Guo , Yue Pan , Jianhua Zhou . Sustained modulation of tumor microenvironment via sorafenib-loaded mesoporous ferromanganese nanozymes for enhanced apoptosis-ferroptosis cancer therapy. Chinese Chemical Letters, 2025, 36(8): 111018-. doi: 10.1016/j.cclet.2025.111018
13. [13]
  Jingyao Yu , Zhuoran Yang , Jian Jiang , Mengshu Xu , Chunyu Yang , Zhuo Li , Wei Guo . Engineering asymmetric electronic structures in Fe-N-S-C nanozymes for dual enzyme-catalyzed-induced ferroptosis and enhanced antitumor efficacy. Chinese Chemical Letters, 2026, 37(3): 111693-. doi: 10.1016/j.cclet.2025.111693
14. [14]
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15. [15]
  Zheng-Biao Zou , Tai-Zong Wu , Chun-Lan Xie , Yuan Wang , Yan Li , Gang Zhang , Rong Chao , Lian-Zhong Luo , Li-Sheng Li , Xian-Wen Yang . neo-Dicitrinols A–C: Unprecedented PKS-NRPS hybrid citrinin dimers with ferroptosis inhibitory activity from the deep-sea-derived Penicillium citrinum W22. Chinese Chemical Letters, 2024, 35(12): 109723-. doi: 10.1016/j.cclet.2024.109723
16. [16]
  Qiuyue Lu , Min Shan , Jiaqi Yang , Zhongren Xu , Yueyue Lei , Wukun Liu . A dinuclear gold(I) complex with bis(N-heterocyclic carbene) ligands potentiated immune responses against liver cancer via ROS-driven endoplasmic reticulum stress and ferroptosis. Chinese Chemical Letters, 2025, 36(12): 110940-. doi: 10.1016/j.cclet.2025.110940
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