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  3. GSTM2 as the molecular linking of depression-driven colon cancer progression and chemoresistance: Reversal by Sinisan

GSTM2 as the molecular linking of depression-driven colon cancer progression and chemoresistance: Reversal by Sinisan

  • Phytomedicine. 2026 Jun:155:158113. doi: 10.1016/j.phymed.2026.158113.
Na Li 1,  Keying Chen 2,  Bin Nie 3,  Fangjun Yu 4,  Anni Ren 2,  Shuquan Yang 3,  Jinlan Zhao 4,  Yanwu Li 2,  Lingling Yang 5,  Shuting Wen 5,  Ying Tang 2,  Pei Xie 6,  Rong Zhang 7,  Huafeng Pan 2,  Zhiyu Wang 8,  Naihua Liu 9,  Yafei Shi 10
Affiliations

Affiliations

  • 1 School of Fundamental Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, China.
  • 2 Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, China.
  • 3 Acupuncture Rehabilitation Department, Guangdong Provincial Second Hospital of Traditional Chinese Medicine, Guangzhou, Guangdong Province, China; Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, Guangdong Provincial Engineering Technology Research Institute of Traditional Chinese Medicine, Guangzhou, Guangdong Province, China.
  • 4 School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, China.
  • 5 Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, and The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, China.
  • 6 Nam Yue Natural Medicine Co., Ltd., Macau, China.
  • 7 Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, China.
  • 8 State Key Laboratory of Dampness Syndrome of Chinese Medicine, Chinese Medicine Guangdong Laboratory, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Academy of Chinese Medical Sciences, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong Province, China. Electronic address: [email protected].
  • 9 Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, China. Electronic address: [email protected].
  • 10 School of Fundamental Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, Chinese Medicine Guangdong Laboratory, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, China. Electronic address: [email protected].
PMID: 41962265 DOI: 10.1016/j.phymed.2026.158113
Abstract

Background: Depression has emerged as a concerning factor in colon Cancer progression and treatment, yet its underlying mechanisms and therapeutic targets remain poorly defined.

Purpose: This study aimed to elucidate how depression affects colon Cancer progression and chemotherapeutic response, and to explore potential molecular targets and therapeutic interventions involving the traditional Chinese medicine formula Sinisan (SNS) and its bioactive component Quercetin.

Study design and methods: A mouse model combining depression and colon Cancer was established to evaluate behavioral alterations, tumor progression, and pathological features. RNA Sequencing was performed to screen the differentially expressed genes. The effects of corticosterone (CORT) on proliferation, colony formation, migration, and GSTM2 expression were examined in HCT116 cells, followed by functional validation through GSTM2 overexpression and inhibition assays. Molecular docking, molecular dynamics simulations, and surface plasmon resonance (SPR) were used to validate the binding of Quercetin to GSTM2. The therapeutic efficacy of SNS and Quercetin was assessed with respect to depressive symptoms, serum BDNF levels, NLRP3 inflammasome activity, and the potency of 5-fluorouracil (5-FU) chemotherapy.

Results: Mice with depression and colon Cancer exhibited aggravated depressive behaviors and accelerated tumor progression. RNA-sequencing and network pharmacology analyses identified GSTM2 as a promising candidate target in colon Cancer treatment, which was markedly down-regulated in the DP-CC group. CORT enhanced proliferation, colony formation, and migration of HCT116 cells while simultaneously suppressing GSTM2 expression. Conversely, GSTM2 levels negatively correlated with cell proliferation, colony formation, and chemoresistance in HCT116 cells. Treatment with SNS alleviated depressive symptoms, elevated serum BDNF, reduced NLRP3 inflammasome activity, and potentiated the efficacy of 5-FU chemotherapy. Quercetin, a bioactive component of SNS, bound to GSTM2 through hydrogen-bond and van-der-Waals interactions, up-regulated GSTM2 expression, and mitigated CORT-induced proliferation, colony formation, and chemoresistance.

Conclusion: Our findings suggest that depression promotes colon-cancer progression by down-regulating GSTM2, whereas SNS restores GSTM2 expression and enhances chemotherapeutic response.

Keywords

Chemotherapy; Colon cancer; Depression; GSTM2; Sinisan.

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