Journal of Clinical Investigation

Following acute kidney injury (AKI), a substantial subset of patients experiences an irreversible progression to chronic kidney disease (CKD), yet the molecular determinants governing this maladaptive transition remain elusive, and effective clinical interventions are lacking. Here, we identify lactate as a key metabolic determinant orchestrating the transition from AKI to CKD. Analysis of the UK…

Immunotherapy resistance remains a challenge in immuno-oncology and predictive biomarkers are needed to guide combination immunotherapy selection for the individual patient. We show that elevated tumor-intrinsic NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) signaling activity correlates with checkpoint inhibitor resistance in several independent cohorts of stage III/IV melanoma and ga…

Insulin resistance (IR) has emerged as a risk factor for lactation insufficiency and delays the onset of milk secretion after childbirth, termed secretory activation (SA). This may cause inadequate infant weight gain and early breastfeeding cessation. However, the mechanisms underlying delayed SA in insulin resistant women are unknown. To investigate this, we characterized the mammary transcripto…

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 …

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 sy…

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 t…

Liver sinusoidal endothelial cells (LSECs) regulate nutrient flux and immune surveillance within the hepatic niche, yet how they function as metabolic stress sensors that instruct adaptive immune remodeling during metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. Here, single-nucleus transcriptomics of human MASLD reveals stage-dependent activation of the cyclic GM…

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, infla…

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)…

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 …

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-cel…

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 t…

Cardiac macrophages (CMs) preserve homeostasis in the heart by clearing cellular debris and facilitating electrical conduction. During tissue injury, embryonically derived CMs (em-CMs) have traditionally been deemed beneficial for promoting tissue repair, whereas monocyte-derived CMs (mo-CMs) are considered detrimental, contributing to inflammation and tissue damage. However, Kasam et al. challen…

Protein neddylation is an evolutionarily conserved posttranslational modification that conjugates NEDD8 to its substrate, catalyzed by an E1-activating enzyme, E2-conjugating enzyme, and E3 ligase. Neddylation is essential for cellular homeostasis, and its dysregulation has been implicated in diverse human diseases, including cancer, neurodegenerative diseases, and metabolic disorders, making the…

Endoplasmic reticulum (ER) stress contributes to β cell death in both Type 1 and Type 2 diabetes (T1D and T2D). However, the molecular mechanisms driving β cell death during ER stress remain insufficiently defined, limiting development of protective therapies. GRP78, an ER chaperone, is the master regulator of unfolded protein response (UPR), suppressing UPR initiators during the unstressed state…

Orphan GPCRs of the GPRC5 family regulate macrophage activity and vascular contractility by dimerizing with other GPCRs, but pharmacological modulation of this process has not been explored. We previously identified the dimerization interface of receptor GPRC5B and show here that both its mutation and inhibition by a decoy peptide disturbed the interaction with the prostaglandin E2 receptor EP2 i…

We reported LINGO1 as a potential marker on Ewing sarcoma cells that could enable targeted drug delivery, improving treatment effectiveness while reducing side effects.

Myxomatous degeneration of the mitral valve (MDMV) is a common cardiovascular manifestation of Marfan syndrome (MFS), yet the role of lymphatic vessels in the disease progression remains unknown. In this Commentary, we discuss the study by Tan, Kume, and colleagues, which identifies defective lymphangiogenesis as a previously unrecognized driver of MDMV. Their work demonstrates that impaired lymp…