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Hydrogen sulfide (H2S), an important gasotransmitter, is involved in a variety of cellular functions and pathophysiologic processes. Drug resistance due to alterations in drug trafficking and metabolism severely limits the effectiveness of cancer therapy. This study examined the role of H2S in drug resistance in liver cancer cells.Human primary hepatocellular carcinoma cell line (HepG2) and doxorubicin (Dox)-resistant cells were used in this study. Cell survival was analyzed by MTT, Annexin V-FITC/propidium iodide staining and clonogenic assay. Western blotting was used for analysis of protein expression, and immunoprecipitation was used to determine interactions of LXR/RXR.The expression of H2S-generating enzyme cystathionine gamma-lyase (CSE) was inhibited by doxorubicin treatment in HepG2 cells, and H2S sensitized Dox-inhibited cell survival and colony formation. In addition, H2S promoted cellular retention of Dox by suppressing the expressions of ABCA1 and ABCG8. H2S significantly blocked Dox-induced heterodimer formation between LXRα and RXRβ and attenuated the binding of LXRα/RXRβ to the promoters of ABCA1 and ABCG8 genes. RXRβ but not LXRα was S-sulfhydrated by H2S, and blockage of RXRβ S-sulfhydration abolished the inhibitory role of H2S on LXRα/RXRβ heterodimer formation. CSE expression was reduced in Dox-resistant cells in comparison with their parental cells, while H2S could reverse drug resistance in Dox-resistant cells.Our study provides a novel solution for reversing drug resistance in cancer cells by targeting H2S signalling.