The　emergence　of　sorafenib　resistance　has　become　a　predominant　impediment　and　formidable　dilemma　in　the　therapeutic　approach　for　hepatocellular　carcinoma　(HCC).　Although　the　approval　of　next-generation　drugs　as　alternatives　to　sorafenib　is　a　significant　development,　the　concurrent　use　of　inhibitors　that　target　additional　key　molecular　pathways　remains　an　effective　strategy　to　mitigate　the　acquisition　of　resistance.　Here,　we　identified　Glutathione　S-Transferase　Alpha　1　(GSTA1)　as　a　critical　modulator　of　sorafenib　resistance　(SR)　in　hepatocellular　carcinoma　(HCC)　based　on　our　findings　from　experiments　conducted　on　recurrent　liver　cancer　tissues,　xenograft　mouse　models,　organoids,　and　sorafenib-resistant　cells.　Elevated　GSTA1　levels　are　strongly　associated　with　adverse　clinical　prognoses.　The　knockout　of　GSTA1　reinstates　sorafenib　sensitivity,　whereas　its　overexpression　attenuates　drug　efficacy.　Mechanistically,　GSTA1　enhances　the　accumulation　of　lipid　peroxides　and　suppresses　ferroptosis　by　exerting　its　peroxidase　function　to　regulate　the　SR.　Notably,　the　upregulation　of　GSTA1　expression　is　mediated　by　the　transcription　factor　CTNNB1　(beta-catenin),　resulting　in　the　formation　of　a　cytoplasmic　complex　between　GSTA1　and　CTNNB1.　This　complex　facilitates　the　nuclear　translocation　of　CTNNB1,　establishing　a　positive　feedback　loop.　The　combined　use　of　GSTA1　and　CTNNB1　inhibitors　demonstrated　synergistic　antitumour　effects　through　the　induction　of　ferroptosis　both　in　vitro　and　in　vivo.　Our　findings　reveal　a　novel　regulatory　role　of　the　GSTA1/CTNNB1　axis　in　ferroptosis,　suggesting　that　targeting　GSTA1　and　CTNNB1　could　be　a　promising　strategy　to　circumvent　sorafenib　resistance　in　HCC.