Long-term spaceflight is known to induce disruptions in circadian rhythms, which are driven by a central pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus, but the underlying molecular mechanisms remain unclear. Here, we developed a rat model that simulated microgravity and isolation environments through tail suspension and isolation (TSI). We found that the TSI environment imposed circadian disruptions to the core body temperature, heart rate, and locomotor-activity rhythms of rats, especially in the amplitude of these rhythms. In TSI model rats’ SCNs, the core circadian gene NR1D1 showed higher protein but not mRNA levels along with decreased BMAL1 levels, which indicated that NR1D1 could be regulated through post-translational regulation. The autophagosome marker LC3 could directly bind to NR1D1 via the LC3-interacting region (LIR) motifs and induce the degradation of NR1D1 in a mitophagy-dependent manner. Defects in mitophagy led to the reversal of NR1D1 degradation, thereby suppressing the expression of BMAL1. Mitophagy deficiency and subsequent mitochondrial dysfunction were observed in the SCN of TSI models. Urolithin A (UA), a mitophagy activator, demonstrated an ability to enhance the amplitude of core body temperature, heart rate, and locomotor-activity rhythms by prompting mitophagy induction to degrade NR1D1. Cumulatively, our results demonstrate that mitophagy exerts circadian control by regulating NR1D1 degradation, revealing mitophagy as a potential target for long-term spaceflight as well as diseases with SCN circadian disruption.

Previous studies have shown that microRNA (miR)‑125b plays important roles in several human cancer types. The aim of the present study was to analyze the potential roles of miR‑125b in papillary thyroid carcinoma (PTC). It was found that miR‑125b was downregulated in PTC and its expression was affected by clinical stages. Glucose transporter 1 (GLUT1) was upregulated in PTC and was negatively correlated with miR‑125b. In PTC cells, overexpression of miR‑125b suppressed glucose uptake and downregulated GLUT1. Furthermore, GLUT1 overexpression reduced the effects of miR‑125b overexpression on glucose uptake. Moreover, miR‑125b overexpression suppressed PTC cell proliferation. GLUT1 overexpression promoted the proliferation of PTC cells and reduced the effects of miR‑125b overexpression on cancer cell proliferation. Overall, miR‑125b decreased glucose uptake in PTC cells by downregulating GLUT1.

BackgroundCastration-resistant prostate cancer (CRPC) remains refractory to immune checkpoint blockade (ICB) due to an immunosuppressive, "cold" tumor microenvironment (TME). Voltage-dependent anion channel 2 (VDAC2) is a mitochondrial outer membrane protein implicated in apoptosis regulation, yet its role in modulating antitumor immunity in CRPC remains elusive.MethodsVDAC2 expression was analyzed in clinical cohorts (TCGA-PRAD and patient specimens). Functional assays, including proliferation, migration, and colony formation, were performed in CRPC cell lines (22Rv1, DU145) following VDAC2 knockdown. Mechanistically, mitochondrial integrity, cytosolic DNA leakage, and cGAS-STING pathway activation were assessed via transmission electron microscopy (TEM), immunofluorescence, and Western blotting. In vivo, the therapeutic efficacy of VDAC2 silencing combined with anti-PD-1 therapy was evaluated using a murine RM-1 subcutaneous xenograft model. Tumor immune infiltration was characterized by flow cytometry and immunohistochemistry.ResultsVDAC2 was significantly upregulated in CRPC tissues and correlated with poor prognosis. Genetic depletion of VDAC2 inhibited CRPC cell proliferation and migration in vitro. Mechanistically, VDAC2 loss triggered BAK-mediated mitochondrial outer membrane permeabilization (MOMP), leading to mitochondrial structural damage and the release of mitochondrial DNA (mtDNA) into the cytosol. This cytosolic mtDNA accumulation activated the cGAS-STING-TBK1-IRF3 signaling axis, subsequently enhancing CD8+ T cell recruitment and cytotoxicity. In vivo, VDAC2 knockdown synergized with PD-1 blockade to robustly suppress tumor growth and prolong survival. This combination therapy remodeled the TME by increasing CD8+ T cell infiltration and effector function while inducing tumor cell apoptosis.ConclusionOur findings identify VDAC2 as a critical mitochondrial checkpoint that restricts innate immune sensing in CRPC. Targeting VDAC2 converts "cold" tumors into "hot" tumors by unleashing mtDNA-mediated cGAS-STING signaling, thereby sensitizing CRPC to PD-1 blockade. This study highlights VDAC2 as a promising therapeutic target to overcome immunotherapy resistance in prostate cancer.