Work

Inhibition of hepatitis B virus through PPAR-JAK/STAT pathway modulation by electroacupuncture and tenofovir disoproxil fumarate combination therapy

Year: 2024

Type: article

Abstract: • Electroacupuncture and tenofovir disoproxil fumarate (E_T) combination therapy effectively inhibits HBV replication in a mice, outperforming tenofovir alone in antigen suppression. • The anti-HBV effect may involve regulation of the PPAR-JAK/STAT pathway, enhancing antiviral molecule expression. • This study highlights the potential of E_T combination therapy as an adjunct treatment for achieving a functional cure in HBV. Acupuncture combined with nucleos(t)ide analogues (NAs) has shown promise in treating chronic hepatitis B (CHB), though mechanisms remain unclear. This study evaluates the antiviral effects of combining acupuncture with NAs against hepatitis B virus (HBV) and explores underlying mechanisms. The HBV-infected mouse model, established using the high-pressure hydrodynamic method, was divided into three groups: normal saline (NS), tenofovir disoproxil fumarate (TF), and electroacupuncture combined with TF (E_T), n = 6. Antiviral effects were assessed by monitoring HBV DNA, HBsAg, and HBeAg levels weekly. Mechanistic insights were gained via transcriptomics, metabolomics, and 16S rDNA sequencing, validated by WB, PCR, and flow cytometry. Serum HBV DNA levels decreased by 1.98 log 10 IU/mL in TF and 2.2 log 10 IU/mL in E_T groups compared to NS. Serum HBeAg decreased by 10.61 % in TF and 35.75 % in E_T, while HBsAg decreased by 7.38 % and 37.58 %, respectively. Multi-omics indicated E_T modulates the PPAR pathway, upregulates taurine and all-trans-retinoic acid, and increases gut microbiota like Bacteroides and Blautia . E_T also enhanced tight junction proteins (ZO-1, Occludin, Claudin-4), improving intestinal barrier integrity. Mechanistically, E_T inhibited the PGC-1α/PPAR-α/SIRT1 pathway, reducing PGC-1α, PPAR-α, SIRT1, RXRα, and HNF4α, while promoting JAK/STAT signaling via IFN-γ, p-JAK1, p-JAK2, p-STAT1, IRF8, and suppressing SOCS-1. E_T more effectively inhibited HBV replication, showing superior antigen inhibition, particularly HBsAg, than TF alone. This may be due to PPAR-JAK/STAT pathway regulation, suggesting E_T as a potential adjuvant therapy for CHB, especially in achieving a functional cure.

Source: International Immunopharmacology

DOI: 10.1016/j.intimp.2024.113304