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In liver transplantation, donor livers are typically stored in a preservation solution at 4°C for up to 12 hours. However, this short preservation duration can lead to various issues, such as suboptimal donor-recipient matching and limited opportunities for organ sharing. Previous studies have developed a long-term preservation method called supercooling liver preservation (SLP) to address these issues. However, in this study using a rat model, we observed that long-term SLP led to more severe liver damage compared with clinically prevalent traditional static cold storage (SCS) for durations less than 8 hours. To understand the potential mechanism of SLP-induced liver injury, we conducted an integrative metabolomic, transcriptomic, and proteomic analysis. We identified the PDE3B-cAMP-autophagy pathway as a key determinant of SLP-induced liver injury. Specifically, we found that PDE3B was elevated during SLP, which promoted a reduction of cAMP metabolites, triggering an AMPK-dependent autophagy process that led to liver injury in rats. We found that blocking the reduction in cAMP using the PDE3B inhibitor cilostamide inhibited autophagy and substantially ameliorated liver injury during 48-hour SLP in rat livers. Furthermore, we validated the effectiveness of cilostamide treatment in preventing liver injury in pig and human liver 48-hour SLP models. In summary, our results reveal that metabolic reprogramming involving the PDE3B-cAMP-autophagy axis is the key determinant of liver injury in long-term SLP and provide an early therapeutic strategy to prevent liver injury in this setting. Editor's summary: Current donor liver preservation methods allow for only 12 hours of organ storage, whereas recently reported liver supercooling has the potential to expand donor liver preservation ex vivo up to several days. Jiao et al. show that current long-term supercooling induces more liver damage than traditional static cold storage at longer hold times through a PDE3B-cAMP–mediated autophagy pathway. Cilostamide treatment of rat, pig, and human livers attenuated this hepatic damage over 48 hours of supercooling, strengthening the prospect of using this approach to greatly expand donor liver storage times before transplanation. —Catherine Charneski [ABSTRACT FROM AUTHOR]

Simple Summary: Type III secretion system (T3SS) is an essential virulence determinant for Vibrio alginolyticus. In this study, we highlighted the significance of T3SS effector protein VopS in the V. alginolyticus infection. The vopS gene, which can promote the virulence of V. alginolyticus to Epinephelus coioides, is required for extracellular protease secretion. Also, it was demonstrated that VopS was involved not only in V. alginolyticus-mediated apoptosis but also in ferroptosis. Collectively, we identified that the VopS effector is a metabolic disruptor, promoting host cell ferroptosis. Vibrio alginolyticus is a Gram-negative pathogen of both marine animals and humans, resulting in significant losses for the aquaculture industry. Emerging evidence indicates that V. alginolyticus manipulates cell death for its pathogenicity, but the underlying molecular mechanisms remain unclear. Here, a gene designated vopS in V. alginolyticus HY9901 was identified, which was predicted to encode the T3SS effector protein. To determine whether VopS contributes to the pathogenesis of V. alginolyticus, the ΔvopS mutant strain was constructed and phenotypically characterized. The deletion of VopS not only reduced the ability to secrete extracellular proteases and virulence but also affected the expression of the T3SS genes. Furthermore, VopS was cytotoxic and induced apoptosis, as confirmed by elevated LDH and the activation of caspase-3. Metabolomic analysis revealed considerable metabolomic disruptions upon V. alginolyticus infection. The VopS effector induced host cell ferroptosis by promoting the synthesis of adrenic acid, depleting cellular glutathione, and subsequently increasing the accumulation of ferrous (Fe2+). Taken together, our findings provide that the VopS effector is an essential virulence factor of V. alginolyticus, which can lead to ferroptosis. [ABSTRACT FROM AUTHOR]