Background and Aims: Immune checkpoint inhibitors have revolutionized systemic HCC treatment. Nevertheless, numerous patients are refractory to immune checkpoint inhibitor therapy. It is currently unknown whether diet therapies such as short-term starvation (STS) combined with immune checkpoint inhibitors can be used to treat HCC. This study aimed to investigate whether STS could sensitize HCC tumors to immunotherapy. Approach and Results: STS was found to attenuate tumor progression by inducing tumor-associated macrophages (TAMs) to switch to an antitumoral phenotype, enhancing phagocytosis of tumor cells, and stimulating subsequent antitumor immunity of CD8 ⁺ T cells as demonstrated in 3 HCC mouse models, NCG mice, and Rag2-KO mice. Furthermore, STS combined with anti-programmed cell death 1/ligand 1 (anti-PD-1/L1) suppressed tumor progression, while the efficacy of PD-L1 was improved when combined with STS. Mechanistically, TAM-derived exosomal PD-L1 (exoPD-L1) impairs the efficacy of anti-PD-1/L1. STS attenuates exoPD-L1 secretion from TAM by regulating the fructose diphosphatase 1 (FBP1) /Akt/Rab27a axis. Modulating FBP1/Akt/Rab27a axis potentiates the anti-PD-L1 response using 2 liposomal delivery systems and macrophage adoptive transfer. Conclusions: This study describes the immunomodulatory effects of STS and provides a rationale for its application as an adjuvant in HCC immunotherapy.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and heart failure (HF) frequently coexist within a shared cardiometabolic environment, yet their mitochondrial abnormalities are stage- and phenotype-dependent rather than uniform. In MASLD, mitochondrial adaptation evolves from increased oxidative metabolism in early steatosis toward impaired respiratory flexibility, oxidative stress, and defective quality control with disease progression, whereas the failing myocardium develops reduced energetic reserve and altered substrate utilization. These organ-specific disturbances can modify mitochondria-linked metabolites, mitochondrial damage-associated molecular patterns, stress-responsive endocrine mediators, and extracellular vesicle-associated mitochondrial cargo. However, similar mitochondrial abnormalities or circulating signals in the liver and heart do not by themselves establish direct inter-organ communication. This review distinguishes shared systemic drivers and organ-intrinsic mitochondrial stress from source-resolved cardio-hepatic signaling, highlighting hepatic ketogenesis, fibroblast growth factor 21 (FGF21), mitochondrial DNA (mtDNA)-dependent inflammatory pathways, and extracellular vesicle-mediated cargo transfer as mechanistically distinct examples with different levels of evidence. We further discuss biomarker limitations, HF-related hemodynamic liver injury, and therapeutic strategies ranging from established cardiometabolic unloading to emerging mitochondria-centered interventions. A stage-, phenotype-, and source-resolved framework may improve interpretation of mitochondrial signals and guide future mechanistic and translational studies in the MASLD–HF overlap.

Mitochondrial distress signaling provides a mechanistic link between local organelle dysfunction and systemic cardio-hepatic remodeling. In metabolic dysfunction-associated steatotic liver disease (MASLD) and heart failure (HF), hepatic nutrient overload and cardiac energy-demand mismatch generate distinct but convergent disturbances in oxidative metabolism, mitochondrial dynamics, mitophagy, and redox control. These changes alter the production, localization, and release of mitochondria-linked metabolites, mitochondrial damage-associated molecular patterns, and extracellular vesicle-associated mitochondrial cargo, enabling stressed tissues to influence distant organs. This review examines how stage-dependent bioenergetic remodeling and defective mitochondrial quality control shape distress-signal generation in MASLD and HF. We further discuss the context-dependent roles of succinate, β-hydroxybutyrate, mitochondrial DNA-dependent innate immune signaling, and extracellular vesicle-mediated cargo transport in heart–liver communication. Finally, we summarize established cardiometabolic therapies and emerging mitochondria-centered strategies that reduce substrate overload, restore organelle resilience, or limit inflammatory signal propagation. Integrating these mechanisms positions mitochondrial distress signaling as a unifying framework for understanding the bidirectional relationship between MASLD and HF and for identifying biomarkers and therapeutic targets at the heart-liver interface.