PloS one · 2026
Auranofin, identified by FDA-approved drug library screening, inhibits HBs antigen secretion via lysosomal damage.
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Shimoda Akiyoshi, Murai Kazuhiro, Hikita Hayato, Minami Satoshi, Miyake Takayuki, Kuriki Shinji, Sometani Emi, Sung Jihyun, Shigeno Satoshi, Higuchi Yuichiro, Maesaka Kazuki, Shirai Kumiko, Tahata Yuki, Saito Yoshinobu, Kodama Takahiro, Takahashi Takeshi, Suemizu Hiroshi, Takehara Tetsuo
Аннотация
BACKGROUND AND AIM: Hepatitis B surface antigen (HBsAg) is associated with hepatocellular carcinoma risk and immune exhaustion and contributes to hepatitis B virus (HBV) persistence. Current anti-HBV treatments have a limited ability to reduce HBsAg levels. This study aimed to identify FDA-approved drugs capable of reducing HBsAg levels and explore the underlying mechanisms.
METHODS: A total of 1134 FDA-approved compounds were screened at 9.9 μM for 7 days using HepG2.2.15.7 cells, which contain an integrated HBV genome. HBsAg in the supernatant and cell viability were assessed. Compounds whose viability was reduced by >1 SD were excluded. Compounds whose HBsAg concentration decreased by >1.5 SD were selected and validated at 0.5 and 5 μM. We evaluated the HBsAg-reducing effect of the final candidate compounds using HBV-infected primary human hepatocytes (HepaSH cells) derived from chimeric TK-NOG mice and investigated the underlying mechanism responsible for the reduction in HBsAg.
RESULTS: After 126 cytotoxic compounds were excluded, the HBsAg levels of the 6 candidates decreased by >1.5 SD. Ethacridine and auranofin significantly reduced the level of HBsAg at both 5 and 0.5 μM. In HepaSH cells, only auranofin decreased the level of HBsAg. Auranofin did not affect the HBe antigen, HBV-DNA, or pregenomic RNA, nor did it reduce the level of intracellular HBsAg, as determined by Western blotting. Transmission electron microscopy revealed more vesicles in auranofin-treated HepaSH cells than in control cells. Immunofluorescence analysis of HepaSH cells treated with auranofin revealed increased Galectin-3 expression and colocalization of HBsAg with Galectin-3, which was consistent with lysosomal damage, compared with those of the untreated controls.
CONCLUSION: Auranofin, an FDA-approved antirheumatic agent, reduces HBsAg secretion via lysosomal damage.
METHODS: A total of 1134 FDA-approved compounds were screened at 9.9 μM for 7 days using HepG2.2.15.7 cells, which contain an integrated HBV genome. HBsAg in the supernatant and cell viability were assessed. Compounds whose viability was reduced by >1 SD were excluded. Compounds whose HBsAg concentration decreased by >1.5 SD were selected and validated at 0.5 and 5 μM. We evaluated the HBsAg-reducing effect of the final candidate compounds using HBV-infected primary human hepatocytes (HepaSH cells) derived from chimeric TK-NOG mice and investigated the underlying mechanism responsible for the reduction in HBsAg.
RESULTS: After 126 cytotoxic compounds were excluded, the HBsAg levels of the 6 candidates decreased by >1.5 SD. Ethacridine and auranofin significantly reduced the level of HBsAg at both 5 and 0.5 μM. In HepaSH cells, only auranofin decreased the level of HBsAg. Auranofin did not affect the HBe antigen, HBV-DNA, or pregenomic RNA, nor did it reduce the level of intracellular HBsAg, as determined by Western blotting. Transmission electron microscopy revealed more vesicles in auranofin-treated HepaSH cells than in control cells. Immunofluorescence analysis of HepaSH cells treated with auranofin revealed increased Galectin-3 expression and colocalization of HBsAg with Galectin-3, which was consistent with lysosomal damage, compared with those of the untreated controls.
CONCLUSION: Auranofin, an FDA-approved antirheumatic agent, reduces HBsAg secretion via lysosomal damage.