The efficacy of immune checkpoint blockade is limited in hepatocellular carcinoma (HCC) due to tumor-intrinsic mechanisms. Here we identify the deubiquitinase MINDY1 as a central regulator of metabolic-immune crosstalk that drives immunotherapy resistance in HCC. MINDY1 is significantly upregulated in immunotherapy non-responders and correlates with poor prognosis and increased M2-like macrophage infiltration. Mechanistically, MINDY1 stabilizes O-GlcNAc transferase (OGT) by removing K48-linked ubiquitin chains, thereby enhancing O-GlcNAcylation of uridine diphosphate glucose pyrophosphorylase 2 (UGP2) at T152. This modification promotes UGP2 enzymatic activity and increases uridine diphosphate glucose (UDPG) synthesis and extracellular accumulation. Tumor-derived UDPG acts as an extracellular immunometabolite that directly binds to PPARγ in macrophages, promoting its nuclear translocation and transcriptional activation. UDPG-driven PPARγ signaling enhances fatty acid oxidation and induces M2-like polarization, suppressing CD8[+] T-cell cytotoxicity and establishing an immunosuppressive tumor microenvironment. Targeting MINDY1 remodels macrophage metabolism, restores CD8[+] T-cell effector function, and significantly enhances anti-PD-1 efficacy in vivo. Our findings uncover a previously unrecognized mechanism that links tumor proteostasis to immune suppression and identify MINDY1 as a promising therapeutic target for overcoming immunotherapy resistance in HCC.

Extended periods of skeletal unloading cause rapid and severe bone loss, structural weakening, and increased fragility. Unlike postmenopausal osteoporosis, disuse bone atrophy is only partially responsive to pharmacological treatments, making it a critical and unresolved medical challenge in both space- and Earth-based medicine. Here, we investigate and assess the dose-response to P7C3 during the transition of bone-derived mesenchymal stem cells to osteoblasts and adipocytes, and its effect during human preosteoclast differentiation into mature osteoclasts in vitro. We further evaluate the in vivo protective properties of P7C3 against pathological bone atrophy induced by mechanical disuse. Data demonstrates that multifunctional P7C3 selectively promoted osteogenesis while inhibiting osteoclast maturation and activity. Proteomic analyses indicate osteogenic augmentation via ↑FSTL-1 and ↓IL-10Rβ, adipogenic inhibition via ↓ADIPOQ and ↑NAMPT, and osteoclastic inhibition via ↓OPN, ↑BMP-7 and ↑OPG. Enrichment analyses suggest the positive regulation of MAPK, JAK/STAT, and Wnt signaling pathways. Transcriptomic data reveal P7C3-induced cell-selective alterations in transcriptional programs within mitochondrial DNA, potentially promoting ATP generation through NADH activity, and regulating cellular energy metabolism. Hindlimb suspension (HLS) induced rapid pathologic bone loss in vivo, with an overarching drive towards adipogenesis (↑C4.A4, ↑FABP3, ↑ADIPOQ, and ↓Dcn) over osteogenesis (↑activin R2A, ↑LIFR and ↓STAT3) and augmented osteoclastic activity and cellular senescence, potentially via MAPK, JAK/STAT, and Wnt signaling. Despite HLS, P7C3 attenuated oxidative stress, RANKL, osteoclastic activity, bone marrow adiposity, cellular senescence, and pathological bone loss. P7C3 presents as an undiscovered and promising multi-target therapeutic strategy against disuse-induced bone atrophy for both space- and Earth-based applications.

Sarcopenic obesity (SO) is a complex age-related phenotype characterized by the concurrent presence of reduced skeletal muscle mass, impaired muscle function, and excessive adiposity, which collectively contribute to metabolic dysfunction, physical decline, and increased mortality. Autophagy maintains cellular homeostasis by regulating protein turnover, mitochondrial quality control, lipid metabolism, and muscle-adipose crosstalk. However, aging, obesity, chronic low-grade inflammation, and insulin resistance may impair autophagic flux, thereby exacerbating muscle degeneration, ectopic lipid deposition, and metabolic imbalance. This narrative review synthesizes current evidence on exercise-modulated autophagic mechanisms in SO and examines how exercise modality, intensity, duration, and individual characteristics shape autophagic responses. Current evidence suggests that exercise may support autophagic homeostasis through multiple mechanisms, including AMPK/mTOR/ULK1, TFEB/FoxO, PGC-1α-related, sirtuin-dependent, and mitophagy-associated pathways. Different exercise modalities appear to confer distinct benefits: resistance exercise primarily promotes muscle anabolism and selective autophagy-related processes; aerobic exercise modulates mitophagy- and lipophagy-related processes; high-intensity interval training may induce rapid, although recovery-dependent, autophagy-related responses; combined exercise may provide a broader metabolic benefit by simultaneously reducing adiposity with muscle preservation. Based on available direct and indirect evidence, long-term, progressive, moderate-intensity resistance exercise combined with aerobic exercise may be a promising strategy for SO management. However, confirmation in SO-specific randomized controlled trials is warranted. Future studies integrating dynamic monitoring of autophagic flux, functional outcomes, and phenotype-stratified exercise prescriptions are needed to translate mechanistic insights into individualized interventions.