Commentary
Abstract
Cancer proteogenomics has revealed that RNA abundance often poorly predicts protein output, highlighting translation as a central determinant of malignant identity. In this issue of JCI, Mishra et al. showed that pharmacologic inhibition of eIF4E cap binding selectively rewired the prostate cancer translatome, suppressing basal keratin translation while promoting luminal features and renewed sensitivity to hormone therapy. More broadly, the study illustrates how tumors exploit selective translation to maintain lineage plasticity, survival, and therapeutic resistance. Targeting translational dependencies may therefore offer a powerful strategy to dismantle cancer-specific proteomic programs and convert resistant cell states into druggable vulnerabilities.
Authors
Davide Ruggero
Abstract
Historically, research on chylomicron entry into intestinal lymphatic vessels (lacteals) has been polarized between paracellular and transcellular transport models. In this issue of the JCI, Sun et al. identified GPR182 as a lipoprotein receptor in lymphatic endothelial cells (LECs), profoundly advancing our understanding of intestinal lipid absorption. They observed poor fat absorption in GPR182-deficient mice and demonstrated the role of GPR182 in transporting chylomicrons across the LECs into the lacteal lumen. This discovery establishes a molecular basis for transcellular transport of chylomicrons, challenging the traditional view that lacteal lipid entry is predominantly paracellular. By linking receptor-mediated uptake to impaired fat absorption and protection against fat-induced obesity and steatosis, this study expands the biological and translational implications of lacteal transport. Consequently, rather than favoring a single model, future research should investigate the integration of both paracellular and transcellular transport models in vivo.
Authors
Liqing Yu
Abstract
Vitiligo is a depigmenting disease marked by progressive T cell–driven destruction of melanocytes in the skin, hair, and mucosa. While vitiligo is known to be a T cell–mediated autoimmune disease, its triggers have remained poorly understood and treatment options limited. In this issue of the JCI, Kang et al. demonstrated how hyperglycemia exacerbates vitiligo progression through the succinate/SUCNR1 axis. These findings identify succinate as a potential biomarker for disease activity and highlight an independent pathway for targeting in therapeutic intervention. More broadly, the findings linking succinate and glucose metabolism to vitiligo suggest that lifestyle factors could be modified to slow development of vitiligo and other autoimmune diseases linked to succinate.
Authors
Kaitlyn G. O’Donnell, I. Caroline Le Poole
Abstract
Traumatic brain injury (TBI) disproportionately kills and disables older adults, yet the biology driving this vulnerability remains unresolved. In this issue of the JCI, Lu et al. combined single-cell transcriptomics, metabolomics, and chromatin profiling in mice, validated in human TBI tissue, to define an age-dependent microglial dichotomy. They report that an NLRP3+/IL-1β–linked state dominates the aged brain, while a Lysozyme+/Lyz2+ state predominates in the young. Microglia-targeted perturbation of NLRP3 and ELF1 each shifted the balance and improved survival in mouse models of TBI, and the repurposed drug Imeglimin improved outcomes in these models, confirming that this pathway is druggable. By connecting NLRP3 inflammasome dominance, ELF1-driven transcription, and glycolytic reprogramming to the loss of a protective Lyz2+ response, this work converts age from a clinical risk factor to a set of druggable microglial targets.
Authors
Josh M. Morganti, Adam D. Bachstetter
Abstract
Cytosolic DNA sensing through the cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway has emerged as a promising strategy to elicit antitumor immunity. However, clinical translation of STING agonists has been hindered by limited efficacy and dose-limiting inflammatory toxicity, highlighting that simply providing activating ligands is insufficient to achieve durable immune responses. In this issue of the Journal of Clinical Investigation, Liao et al. showed that intracellular aspartate availability critically shapes STING signaling responsiveness. Aspartate deficiency disrupted pyrimidine synthesis, induced mtDNA stress, and engaged a feed-forward Z-DNA binding protein 1 and receptor interacting serine/threonine kinase 1/3 axis. Rather than directly triggering immunity, this metabolic state primed DNA sensing and fueled downstream signaling, thereby enabling robust and sustained antitumor immune responses. Together, these findings position nucleotide metabolism as a key determinant of innate immune responsiveness and suggest that metabolic conditioning may enhance the efficacy of STING-targeted therapies.
Authors
Haitao Jiang, Wenyan Wang, Yang-Xin Fu
Abstract
Liver fibrosis is a common pathological outcome of chronic liver disease and is driven by inflammatory responses. However, the early signals that initiate the inflammatory cascade remain poorly understood. Emerging evidence suggests that liver sinusoidal endothelial cells (LSECs) are not merely passive bystanders, but active regulators during liver fibrosis. In this issue of the JCI, Gan et al. demonstrated in multiple preclinical models that BRD4/PML-mediated super-enhancer activation in LSECs drives proinflammatory angiocrine signaling, thereby initiating liver fibrosis. Thus, targeting this endothelial axis may offer a promising therapeutic strategy for the treatment of liver fibrosis.
Authors
Yingfen Chen, Yong He
Abstract
The Western diet (WD) is a rich source of saturated fatty acids, especially palmitic acid (PA), which has been implicated in the pathogenesis of insulin resistance, oxidative stress, inflammation, diabetes, and multiorgan dysfunction in obesity and diabetes. In this issue of the JCI, a study by Balasubramaniam et al. describes mechanisms linking a WD, PA, ferroptosis (iron-dependent cell death), and loss of colonic motility. Chronic PA exposure drove ferroptosis in murine in vitro systems and human myenteric ganglia. Mice fed a WD for 12 weeks developed enteropathy and loss of colonic motility, which was reversed by adeno-associated virus–mediated (AAV-mediated) overexpression of the transcription factor NFE2L2, preventing ferroptosis and restoring redox balance to enteric neurons. The study provides critical data establishing PA-induced ferroptosis as a mediator and potential therapeutic target in enteric nervous system disorders associated with obesity.
Authors
Rexford S. Ahima
Abstract
Cancer cachexia, characterized by weight loss, muscle wasting, and anorexia, complicates cancer treatment and adversely affects patient outcomes. Both tumor-derived and host inflammatory factors are implicated in aspects of cachexia. The search for circulating mediators of cancer cachexia has focused largely on secreted proteins, but metabolites may also drive systemic wasting. In this issue, Morigny, Rohm, and colleagues identified the liver as a major source of circulating ceramides in cachectic mice and patients with cancer and demonstrated that inhibiting ceramide synthesis attenuated muscle wasting and preserved function in cachectic mice. These findings position the liver as an endocrine organ in cachexia and introduce a druggable metabolic pathway with translational potential.
Authors
Kerui Huang, Norbert Perrimon, Marcus D. Goncalves
Abstract
Glioma stem cells (GSCs) are a small subset of self-renewing, plastic, and multipotent neoplastic cells in glioblastoma (GBM) that sit at the apex of a cellular differentiation hierarchy. Elucidating pathways that enhance GSC properties and determine their cell-specific interactions within the immunosuppressive GBM microenvironment are critical for developing effective therapeutic approaches. The CLOCK-BMAL1 complex, which is well known for its activity as a circadian rhythm–regulating transcription factor, plays a critical role in maintaining GSC stemness, and the gene encoding CLOCK was found to be amplified in about 5% of GBM cases. Here, Zhou et al. have uncovered a “symbiotic exclusivity” relationship between CLOCK-BMAL1 and TFPI2, which is also amplified in a small proportion of GBM cases. This relationship forms a HIF-1α/NF-κB P65–mediated positive feedback loop that boosts the proliferative and tumor-enhancing capacities of GSC and immunosuppressive microglia. This self-amplifying regulatory circuit represents an opportunity for intervention to inhibit GBM growth.
Authors
Petros Basakis, Ling-kai Shih, Jiabo Li, Daniel J. Brat
Abstract
Clinical management of pancreatic cancer (PC) remains severely limited, primarily due to the complex tumor microenvironment. Emerging DNA damage–targeted strategies have demonstrated considerable therapeutic potential in PC. In this issue of the JCI, Teh et al. employed cancer-specific multitarget sgRNAs to induce DNA double-strand breaks (DSBs), resulting in lethal effects in PC cells. Integrative bioinformatic and cytogenetic analyses revealed that CRISPR/Cas9-mediated DSBs provoked persistent chromosomal instability, ultimately leading to chromosome catastrophe and cell death. Compared with equivalent radiation-induced DSBs, these sgRNAs exhibited superior cytotoxicity and were able to eliminate cells resistant to a specific sgRNA via subsequent targeting at distinct genomic sites, highlighting a promising and innovative precision therapeutic approach for clinical treatment of PC.
Authors
Li-Chan Chang, Christine E. Eyler, Chang-Lung Lee
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