S-palmitoylation, a reversible post-translational modification regulates protein stability and cellular functions, yet its role in glutamine metabolism remains unclear. Here, we show that ZDHHC14 as the key palmitoyltransferase catalyzing ASCT2 palmitoylation at conserved Cys39 and Cys48 residues, promoting lysosomal degradation of this glutamine transporter, whereas ABHD17B functions as a depalmitoylase to stabilize ASCT2. Mechanistically, glutamine deprivation activates JNK1, which directly phosphorylates ZDHHC14 at Thr440 residue, triggering its degradation and thereby enhancing ASCT2 stability. Importantly, combination of JNK and ASCT2 inhibitors synergistically inhibits glutamine metabolism and tumor growth in vivo. These findings reveal a phosphorylation-palmitoylation axis linking JNK-mediated ASCT2 palmitoylation and glutamine metabolism, offering a potential therapeutic strategy for non-small cell lung cancer.

c-Myc is broadly hyperactivated in colon cancer, yet the mechanisms sustaining its transcriptional activation remain elusive. Here we identify palmitic acid (PA) as a metabolite cue that activates c-Myc via dual palmitoylation-dependent pathways operating across tumor initiation and progression. In colitis models, PA-rich diets exacerbate inflammation and enrich MYC target programs without increasing Myc mRNA. Mechanistically, the palmitoyltransferase ZDHHC9, upregulated by IL-1β, directly palmitoylates c-Myc at C171, enhancing c-Myc/MAX dimerization and transcriptional activity; genetic or pharmacologic inhibition diminishes c-Myc palmitoylation and target gene expression. During tumor progression, c-Myc transactivates FATP2, increasing PA uptake and reinforcing c-Myc palmitoylation, thereby establishing a feedforward loop and metabolic addiction to PA. Functionally, PA accelerates xenograft growth, whereas targeting ZDHHC9 and FATP2 inhibits c-Myc function to suppress tumor burden. These findings uncover metabolite-driven control of c-Myc through palmitoylation and highlight ZDHHC9/FATP2 as actionable vulnerabilities for colon cancer treatment.

Neurotropic viruses invade neural tissues, resulting in severe diseases such as poliomyelitis, rabies, herpesviral encephalitis, and viral meningitis. Given this neurotropism, we investigated whether the infection of the host by these viruses is under circadian control. In this study, we found that the expression of most neurotropic virus receptors exhibits rhythmicity across cells, cerebral organoids, and animal models, with host cell susceptibility modulated by the circadian clock. We identified E2F8 as a clock-controlled gene that mediates the indirect regulation of the circadian clock on neurotropic viruses. Notably, E2F8 regulated the expression of core clock components by binding directly to the promoters of REV-ERBα and PER2, suggesting its role as a potential modulator of circadian rhythms. Additionally, we revealed a seldom-recognized viral strategy to accelerate viral replication in the host: rabies virus disrupts the host circadian clock system primarily through its glycoprotein hijacking the E3 ubiquitin ligase HUWE1 to inhibit proteasomal degradation of REV-ERBα. These findings increase our understanding of the interactions between circadian systems and neurotropic viral dynamics and highlight the potential of chronotherapy for improved antiviral treatments.

Deciphering the spatial organization of cell states is fundamental for understanding development, tissue homeostasis and disease. Emerging advances in spatial transcriptomic profiling techniques allow transcript localization but face limitations in unambiguous cell state assignments due to cellular boundary inference, low gene detection and prohibitive cost. Here, a method, Stamp-seq, is developed that leverages custom-fabricated high-density DNA sequencing chips to label single nuclei with restriction enzyme-cleavable spatial barcodes. Stamp-seq spatial barcodes are distributed at a density of 1.6 μm on the chip, allowing for single physical cell resolution with precise subtype classification and spatial mapping (with an average 4 μm localization error) and reduced cost. We utilize Stamp-seq to delineate chemoimmunotherapy-responsive cellular ecosystems in non-small cell lung carcinoma, including a distinct IGHG1+ plasma cell-enriched community. Through a novel application of Stamp-seq to spatially resolve BCR clonotypes, we elucidate the spatiotemporal trajectory of treatment-potentiating IGHG1+ plasma cells, which originate from tertiary lymphoid structures (TLSs) or the vasculature, migrate through antigen-presenting CAF (apCAF)-enriched survival niches, and ultimately contact tumor cells. We highlight the power of spatial cellular subtyping and molecular tracking using Stamp-seq and suggest that the IGHG1+ plasma cell niche is a better prognostic biomarker for the chemoimmunotherapy response.

Deeper insights into omics in the clinical and tumor microenvironments of lung adenocarcinoma (LUAD) could reveal therapy-sensitive subtypes and novel treatments. From a cohort of 1008 samples from Chinese patients with LUAD with whole-genome and transcriptome sequencing data along with comprehensive longitudinal clinical and therapeutic information, we identified four prognostically distinct subtypes, namely, low proliferation and invasion (LPI), immune-desert (IMD), immune-enriched (IME), and high proliferation and invasion (HPI), based on the transcriptomic features linked to the radiological, pathological, and microenvironmental dimensions. Compared with chemotherapy, tyrosine kinase inhibitor (TKI) therapy demonstrated significantly superior efficacy for LPI and IMD, whereas no such difference was observed for HPI. VOPP1 and RRM2B amplification were closely associated with TKI resistance and sensitivity, respectively. VOPP1 knockdown restored sensitivity to TKI treatment, while RRM2B knockdown induced TKI resistance, and its overexpression restored sensitivity. Patients with RRM2B amplification had a 5-year survival rate of nearly 100%. Additionally, the IME subtype exhibited higher immune checkpoint activity and a higher frequency of DYNC2H1 mutation, with patients benefiting from immunotherapy. These findings provide critical insights into LUAD treatment optimization.

Aging impairs the regenerative capacity and differentiation potential of human adipose-derived stem cells (hASCs), but the mechanisms underlying their functional decline remain unclear. Through systematic functional assays and in vivo experiments, we first confirmed age-associated reductions in hASC self-renewal, lineage plasticity, and tissue repair efficacy. By integrating multiomics profiling and functional validation, we identified a metabolically active ACTA2+TAGLN+ subpopulation that was enriched mainly in infant-derived hASCs (I-hASCs) and characterized by increased catabolism of branched-chain amino acids (BCAAs) and glutamine. Mechanistically, the RNA-binding protein IGF2BP3, which is predominantly expressed in the ACTA2+TAGLN+ subpopulation, sustains hASC stemness by stabilizing BCAT1 and GLS mRNAs via METTL3-mediated m6A modification, thereby preserving redox homeostasis and mitochondrial energy production. Furthermore, age-related attenuation of the IGF2BP3-m6A-BCAT1/GLS axis contributed to metabolic reprogramming, driving senescence-associated functional collapse in elderly-derived hASCs (E-hASCs). Strikingly, rescue experiments demonstrated that genetic restoration of BCAT1/GLS or supplementation with BCAAs/glutamine significantly rejuvenated E-hASCs, restoring their proliferation, differentiation, and in vivo wound-healing capacities. These findings identify IGF2BP3 as a central regulator of hASC aging by linking m6A epitranscriptomic modifications to metabolic reprogramming and establish the IGF2BP3-m6A-BCAT1/GLS axis as a druggable node in aged hASCs. This study proposed two therapeutic strategies: nutrient supplementation to rescue metabolic deficits and m6A modulation to stabilize key mRNAs, providing a clinically feasible protocol to optimize elderly-derived hASCs for tissue regeneration.

Osteoclasts are bone-resorbing cells that play a central role in normal bone remodeling and contribute to bone loss associated with pathological conditions such as osteoporosis, osteoarthritis, rheumatoid arthritis, periodontal disease, and bone metastases of cancer. The commitment, differentiation, and function of osteoclasts depend on the establishment of specific gene expression patterns orchestrated through a network of transcription factors, which are sequentially activated by osteoclastogenic signals. This review provides an updated overview of the roles of key signaling pathways (e.g., RANKL signaling, NF-κB signaling and Gα13 signaling), transcription factors (e.g., PU.1, C/EBP-α, NFATc1 and IRF8), cytokines (e.g., TNF-α, IL-1β and IL-6), and epigenetic regulators (e.g., DNMT3a, EZH2 and ASXL1) in osteoclast lineage commitment, differentiation and bone resorption under both physiological and pathological inflammatory conditions, along with insights from corresponding mouse models. We described the mechanism by which osteoclast-mediated bone resorption occurs through extracellular acidification driven by osteoclast-specific proton pump subunits (e.g., ATP6i and ATP6v0d2), followed by matrix protein degradation mediated by cathepsin K and MMP-9. Additionally, this review examines the interplay among molecular mechanisms that regulate osteoclast differentiation and activation under pathological and inflammatory conditions, elucidates their roles in osteoclast hyperactivation-related human diseases, and provides a comprehensive framework for understanding these processes. Finally, it underscores potential novel therapeutic strategies for osteoclast-related skeletal lytic diseases and highlights perspectives for future investigations.