An herbal formula Shenlian decoction upregulates M1/M2 macrophage proportion in hepatocellular carcinoma by suppressing complement cascade

  • Biomed Pharmacother. 2024 Jun 14:177:116943. doi: 10.1016/j.biopha.2024.116943.
Wenxuan Li  1 ,  Liping You  1 ,  Jiacheng Lin  2 ,  Jinghao Zhang  3 ,  Zhijia Zhou  1 ,  Tao Wang  1 ,  Yuelan Wu  1 ,  Chao Zheng  3 ,  Yueqiu Gao  4 ,  Xiaoni Kong  5 ,  Xuehua Sun  6
Affiliations
  • 1. Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China; Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • 2. Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • 3. Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • 4. Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China; Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China. Electronic address: [email protected].
  • 5. Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China. Electronic address: [email protected].
  • 6. Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China. Electronic address: [email protected].
PMID: 38878636 DOI: 10.1016/j.biopha.2024.116943
Abstract

The immunosuppressive microenvironment is a vital factor for the hepatocellular carcinoma (HCC) progression. However, effective treatment is lacking at current. Shenlian decoction (SLD) is a registered herbal therapy for the HCC treatment, but the underlying mechanism of SLD remains largely elusive. Here, we aimed to explore the anti-tumor effect of SLD in the treatment of HCC. SLD was intragastrically given after the tumor initiation in β-catenin/C-Met or DEN and CCl4 induced HCC mouse model. The tumor growth levels were evaluated by liver weight and histological staining. The tumor-infiltrating immune cells were detected by immunological staining and flow cytometry. The mechanism of the SLD was detected by non-targeted proteomics and verified by a cell co-culture system. The result showed that SLD significantly attenuated HCC progression. SLD promoted macrophage infiltration and increased the M1/M2 macrophage ratio within the tumor tissues. Non-targeted proteomics showed the inhibition of complement C5/C5a signaling is the key mechanism of SLD. Immunological staining showed SLD inhibited C5/C5a expression and C5aR1+ macrophage infiltration. The suggested mechanism was demonstrated by application of C5aR1 inhibitor, PMX-53 in mouse HCC model. Hepatoma cell-macrophage co-culture showed SLD targeted hepatoma cells and inhibited the supernatant-induced macrophage M2 polarization. SLD inhibited AMPK/p38 signaling which is an upstream mechanism of C5 transcription. In conclusion, we found SLD relieved immune-suppressive environment by inhibiting C5 expression. SLD could suppress the C5 secretion in hepatoma cells via inhibition of AMPK/p38 signaling. We suggested that SLD is a potential herbal therapy for the treatment of HCC by alleviating immune-suppressive status.

Keywords
Complement cascade; Hepatocellular carcinoma; SLD; Tumor-associated macrophages.
Products