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Abstract
Transfer RNA (tRNA) modifications play a critical role in regulating codon-specific mRNA translation and enabling tumor cell adaptation. The RNA methyltransferase METTL1 installs N7-methylguanosine (m⁷G) modifications on tRNAs, thereby shaping codon usage and translational output. However, the function and mechanistic contribution of the METTL1–tRNA axis in pancreatic ductal adenocarcinoma (PDAC) remain poorly defined. Here, we show that METTL1 is overexpressed in PDAC tissues and that elevated METTL1 expression is associated with poor patient survival. Genetic ablation of METTL1 markedly suppresses PDAC cell proliferation, migration, and tumor growth in vitro and in vivo. Mechanistically, METTL1 loss selectively reduces m⁷G-modified valine tRNAs – particularly, Val-AAC, Val-CAC, and Val-TAC – leading to impaired translation of valine-enriched oxidative phosphorylation transcripts. As a consequence, METTL1 deficiency disrupts mitochondrial respiration and energy production in PDAC cells. Consistent with this model, valine tRNA levels are elevated in PDAC tissues, and their selective depletion phenocopies METTL1 loss by impairing mitochondrial bioenergetics and tumor cell fitness. Thus, the METTL1–valine tRNA axis promotes PDAC progression through codon-dependent translational control of mitochondrial electron transport chain and oxidative metabolism. Together, our findings identify a METTL1–tRNA–mitochondrial signaling axis as a previously unrecognized metabolic vulnerability and a promising therapeutic target in pancreatic cancer.
Authors
Jiabei Zhu, Qi Zhang, Douglas Evans, Rui Su, Qiuhui Pan, Ajay Goel
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a global health concern. Nevertheless, its underlying pathological mechanisms remain poorly understood. Here, we showed that E3 ubiquitin ligase ring finger protein 10 (RNF10) protein levels were positively correlated with MASLD in both mice and humans. Hepatic-specific Rnf10 deletion attenuated liver steatosis, inflammation, and fibrosis. Conversely, adeno-associated virus (AAV)-mediated hepatic-specific Rnf10 overexpression exacerbated MASLD-related phenotypes. Mechanistically, RNF10 interacted with carnitine palmitoyltransferase 1A (CPT1A) and facilitated its degradation through K48-linked ubiquitination, thereby inhibiting fatty acid oxidation, promoting hepatic lipid accumulation, and ultimately exacerbating liver inflammation and fibrosis. Moreover, we utilized triantennary N-acetylgalactosamine (GalNAc) to deliver small interfering RNA (siRNA) specifically targeting Rnf10 to hepatocytes. This approach effectively ameliorated diet-induced liver steatosis, inflammation, and fibrosis in mice. Therefore, interfering with the expression or function of RNF10 may be a promising therapeutic strategy for MASLD.
Authors
Chunyuan Du, Yinliang Zhang, Hongkai Chang, Chaofan Xu, Sufang Sheng, Ke Xu, Wei Qiao, Yanjun Liu, Tongtong Zhang, Yong Gao, Peng Li, Yongsheng Chang
Abstract
Authors
Seyi E. Elasoru, Christian Miccile, Jingwu Pan, Zhaoyang Zhang, Kalyanam Shivkumar, Herbert Herzog, Robert D. Harvey, Zhilin Qu, Olujimi A. Ajijola
Abstract
Intestinal lipid metabolism is essential for systemic energy homeostasis, and its modulation is emerging as a therapeutic strategy for obesity. Menin, a scaffold protein that regulates chromatin remodeling and gene expression, is abundantly expressed in intestinal epithelial cells (IECs), but its metabolic role remains underexplored. Here, we generated IEC-specific Men1 knockout mouse and found that Men1 deficiency protected against high-fat diet-induced obesity, accompanied by elevated carboxylesterase 1 (CES1) expression in IECs. Increased CES1 promoted triglyceride (TG) hydrolysis and reduced intracellular TG storage, thereby limiting the lipid substrate pool required for ApoB48-dependent chylomicron assembly. Although lipid hydrolysis was enhanced, steady-state free fatty acid levels were not increased; instead, Men1 deficiency activated fatty acid β-oxidation programs and increased etomoxir-sensitive fatty acid–dependent mitochondrial respiration, supporting enhanced fatty acid catabolism. Mechanistically, menin recruited histone deacetylase 1 and interacted with the nuclear receptor LXRβ to suppress Ces1g transcription, thereby sustaining efficient intestinal lipid absorption. Pharmacological inhibition of menin with MI-463 recapitulated the metabolic effects of inducible Men1 deletion. In a human gut organoid-on-chip system, MI-463 dose-dependently increased CES1 expression and markedly reduced lipid accumulation. Collectively, our findings identify menin as a regulator of intestinal lipid metabolism and suggest menin inhibition as a potential therapeutic strategy for obesity-related metabolic disorders.
Authors
Xiaoru Cao, Pingping Zhou, Haiyue Meng, Zhitao Guo, Yan Cao, Chenghao Wang, Lulu Liu, Yinghao Guo, Yue Wang, Guoshun Xin, Dabin Liu, Feng Geng, Jian Ma
Abstract
Aneuploidy is a hallmark of cancer often associated with inferior prognosis. Copy number gains of chromosome 8 (chr8) are recurrent in multiple cancers, including breast, prostate, colorectal cancers, and sarcomas such as malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are aggressive, hard-to-treat sarcomas frequently linked to the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome. To investigate the role of chr8 gain in MPNST pathogenesis, we performed a CRISPR knockout screen and identified 58 essential genes on chr8, including PTK2, which encodes focal adhesion kinase (FAK). We evaluated FAK as a therapeutic target and tested small-molecule FAK inhibitors (FAKi) alone or combined with RAF/MEK inhibitors (RAF/MEKi), a class of agents relevant to NF1-deficient tumors with ERK pathway hyperactivation. Both pharmacological and genetic inhibition of FAK reduced MPNST cell proliferation in vitro and tumor growth in vivo. Combined FAKi and RAF/MEKi treatment further suppressed phosphorylation of FAK, STAT3, and AKT while increasing cleaved caspase-3 and PARP-1, indicating enhanced apoptosis. In MPNST patient-derived xenograft (PDX) models, combination therapy significantly reduced tumor growth, showing superior efficacy, particularly in chr8 gain MPNST-PDX. These results support FAK/RAF/MEK co-targeting as a promising therapeutic strategy for chr8 gain MPNST and related tumors.
Authors
Guangfeng Wang, Dana C. Borcherding, Jiawan Wang, Xiaochun Zhang, Liuzhan Yang, Gorkem Oztosun, James J. Sears, Kangwen Xiao, Belinda B. Garana, Mark I. Zoberi, Aaron U. Bektas, Jeffrey J. Szymanski, Richa Rathore, Silvia Coma, Jonathan A. Pachter, Sara J.C. Gosline, Christine A. Pratilas, Angela C. Hirbe
Abstract
Hereditary Hemorrhagic Telangiectasia type 2 (HHT2), caused by mutations in ACVRL1 ( also known as ALK1), is characterized by brain arteriovenous malformations (bAVMs), abnormal artery–vein connections for which treatment options remain limited. Despite evidence of endothelial cell (EC) heterogeneity, its role in bAVM pathogenesis remains poorly defined. Using endothelial-specific inducible Alk1 knockout mice (Alk1iECKO) and regionally resolved single-cell RNA sequencing, we show that loss of ALK1 signaling induces bAVMs predominantly in the perineural vascular plexus (PNVP). This process is driven by the emergence of a KIT+ angiogenic EC population with human AVM-like transcriptional features, including tip-cell markers and activation of PI3K and KRAS signaling pathways. Cross-species analyses and validation in human samples demonstrate that KIT expression is conserved in endothelial cells from both sporadic and HHT2 brain AVMs. Drug repurposing analysis identified KIT as a top actionable target, and we show that Kit is directly repressed by BMP9–ALK1–SMAD4 signaling. Pharmacological inhibition of KIT reduced angiogenic reprogramming and vascular malformations in vivo without affecting normal vasculature. These findings identify a pathogenic angiogenic EC state and position KIT signaling as a therapeutically actionable pathway in brain AVMs.
Authors
Elise Drapé, Lauranne Carrier, Gael Cagnone, Atik R.M. Fuad, Mathilde Bizou, Damian A. Sanchez, Typhaine Anquetil, Jack Wang, Halima Drissi Touzani Walali, Adnan Gopinadhan, Patrick Piet van Vliet, Joel P. Howard, Mysha Ibnat, Gregor Andelfinger, Ethan Winkler, Bruno Larrivée, Alexandre Dubrac
Abstract
The endocardium is a major source of coronary angiogenesis and arterialization, through coordinated cell fate transition and migration. However, the transcriptional regulatory network synchronizing cell fate determination and movement remains unclear. Here, we identified transcription factor HAND2 as a key candidate for coronary vascular formation. Endocardial deletion of Hand2 in mice disrupted arterial-venous networks and stunted coronary arteries, paralleling a ventricular noncompaction phenotype. Moreover, deletion of Hand2 produced excessive tip cells with defective movement. RNA-seq analysis revealed enhanced hypoxic metabolic activation but declined TGF-β/p38MAPK-dependent endothelial-to-mesenchymal transition (Endo-MT). In consistence, genetic inhibition of the core hypoxic regulators or pharmaceutical administration of TGFβ2 partially recovered the coronary arterial defects in Hand2 mutants. Furthermore, HAND2 was found directly bound to promoters of the target genes, harmonizing cell migration and cell fate transition. These findings pinpoint HAND2 as an essential regulator of the endocardial transcriptional regulatory network for coronary arterialization and provide potential therapeutic targets for coronary artery diseases.
Authors
Huijuan Wang, Haosheng Zhang, Leiyin Zheng, Peihan Zhang, Yuqian Wang, Sijia Ding, Wenping Liu, Yuanming Cheng, Zhongzhou Yang, Wen Luo
Abstract
Polyendocrine metabolic ovarian syndrome (PMOS), formerly known as polycystic ovary syndrome (PCOS), is the most common endocrine disorder in women and is closely associated with complex diseases such as cardiovascular disease and type 2 diabetes. However, the mechanistic links between PMOS and its comorbidities remain poorly understood. Here, we present an integrative systems genetics platform that leverages genetic diversity in both mice and humans to dissect the drivers of PMOS and its associated complications. This framework uncovers conserved genetic and environmental factors underlying PMOS, identifies susceptible cell types and organs, and elucidates mechanisms linking PMOS to subsequent pathologies. For instance, we show that increased ovarian area contributes to both PMOS susceptibility and ovarian cancer progression, while specific ovary–heart signaling circuits modulate cardiac function with aging. We further identify ovarian SF3B1-mediated alternative splicing as a key mechanistic link between PMOS and metabolic traits. Pharmacologic inhibition of SF3B1 in mice reduced circulating testosterone, insulin and glucose levels, as well as fat mass expansion. Transcriptomics analysis of ovaries from mice and experiments using human cell lines localized these effects to exon skipping events in granulosa cells. Together, this study offers a mechanistic framework for modeling the diversity of PMOS pathologies and uncovers SF3B1-mediated splicing as a link between ovary function and systemic metabolism.
Authors
Christy M. Nguyen, Leandro M. Velez, Youngseo Cheon, Cimone L. Jackson, Casey D. Johnson, Ian Tamburini, Mingqi Zhou, Erik Alvstad, Isoo Yoon, Farheen Dustagheer, Marie Li, Tvisha Gujjarlapudi, Kaitlene Ofilan, Neha Mishra, Evan G. Williams, Danica Kwan, Carlos H. Viesi, Naveena Ujagar, David G. Ashbrook, Alistair Senior, Marin E. Nelson, Nicholas R. Pannunzio, Selma Masri, Evgeny Kvon, Grant MacGregor, Cholsoon Jang, Vittorio Sebastiano, Minji Byun, Changrui Xiao, Alexander S. Kauffman, Robert W. Williams, David E. James, Ivan Marazzi, Dequina Nicholas, Marcus Seldin
Abstract
Hepatocellular carcinoma (HCC) is heterogeneous, and hepatocyte plasticity is linked to poorer patient outcomes. A subset of human HCC harboring Tuberous Sclerosis Complex 1 (TSC1) mutations exhibits more aggressive behavior. TFEB is a master regulator of lysosomal biogenesis and cell fate. We analyzed human normal and HCC tissue arrays for TFEB and CK19 expression, as well as bulk and single-cell RNA-seq datasets from mouse and human HCC, to define TFEB-associated transcriptional programs. We performed biochemical, histological, metabolomic, and transcriptomic analyses in liver-specific Tsc1 knockout (L-Tsc1 KO) and L-Tsc1,Tfeb double KO (DKO) mice. Loss of hepatic Tsc1 led to increased phosphorylation of S6 and 4EBP1, with paradoxical increases in TFEB nuclear translocation and activation. L-Tsc1 KO mice showed increased hepatocyte plasticity, decreased HFN4α, increased YAP1 activation, and spontaneous HCC with increased SOX9 and CK19-positive biliary epithelial cell (BEC)-like cells at 8-12 months. Deletion of Tfeb dampened hepatic metabolic reprogramming and hepatocyte fate changes and inhibited tumor progression in L-Tsc1 KO mice. Increased TFEB activity was associated with increased YAP and SOX9 gene expression and high-grade malignant HCC in humans. These findings indicate that loss of hepatic TSC1 leads to non-canonical TFEB activation, promoting hepatocyte plasticity and tumor heterogeneity associated with high-grade malignancy in both mouse and human HCC.
Authors
Chen Zhang, Xiaojuan Chao, Sha Neisha Williams, Xiaoli Wei, Anthony DiGirolamo, Alisha Bajracharya, Lichun Ma, Ming Huang, Nicholas Dunn, Wanqing Liu, Kaito Ueda, Masayuki Sugimoto, Andrea Ballabio, Hong-Min Ni, Wen-Xing Ding
Abstract
Authors
Yashika Parashar, Zsofia Sztupinszki, Aurel György Prósz, Xiaolu Wang, Pratyusha Bala, Shweta Kiran Cavale, Chinedu Ukaegbu, Sapna Syngal, Asaf Maoz, Leah H. Biller, Ramona Lim, Matthew B. Yurgelun, Zoltan Szallasi, Nilay S. Sethi
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ISSN: 0021-9738 (print), 1558-8238 (online)