BACKGROUND: Talaromyces marneffei (T. marneffei), a life-threatening opportunistic fungal pathogen, is endemic to Southeast Asia. Although elevated aspartate aminotransferase (AST) levels are commonly observed in infected individuals, the origin and mechanism of this phenomenon remain unclear. This study aimed to determine whether AST is a specific clinical indicator of T. marneffei infection and to investigate the underlying mechanisms associated with tissue damage and cell death. METHODS: We retrospectively analyzed clinical and laboratory data of HIV/AIDS patients with or without T. marneffei infection from the Fourth People's Hospital of Nanning, Guangxi. A murine model of T. marneffei infection was constructed to investigate AST distribution in tissues. Additionally, PANoptosis-related proteins expression and inflammatory cytokines levels were assessed using ELISA, qPCR, and Western blotting. RESULTS: Patients with HIV/ T. marneffei co-infection demonstrated significantly higher serum AST levels than HIV-only individuals, which declined following antifungal therapy. In infected mice, AST levels increased progressively in plasma and organs, with hepatic levels elevated throughout days 7, 14, and 21 post-infection. The liver exhibited the highest AST concentration, while the spleen showed the greatest fold increase. PANoptosis markers, including P-RIP, RIPK1, RIPK3, P-MLKL, GSDME, GSDMD, cleaved GSDMD, caspase-3, caspase-7, caspase-8, caspase-9, were markedly upregulated in liver tissues. Concurrently, proinflammatory cytokines Tnf-α, Il-1β, and Il-18 were consistently elevated in the liver but suppressed in the spleen, indicating organ-specific immune responses. CONCLUSIONS: Our findings demonstrate that T. marneffei infection triggers PANoptosis- mediated hepatocyte death and hepatic inflammatory activation, which contributes to AST elevation. AST may serve as a potential auxiliary biomarker for early diagnosis and therapeutic monitoring in Talaromycosis.