Commentary
Abstract
Bone formation in soft tissues, known as heterotopic ossification (HO), can occur as a complication of trauma or burn injury and can cause pain and functional limitations in the affected site. HO remains an unmet clinical challenge due to a general lack of specific medical therapies. In this issue of the JCI, a study by Moye et al. identified obesity as a risk factor for HO and further found that the association with obesity was driven not by caloric surplus, but instead by dietary omega-6 lipids, which are characteristically elevated in the Western diet. These omega-6 lipids accumulated directly at the incipient HO site, where they served as substrates for prostaglandin E2 (PGE2), fueling aberrant osteoblast differentiation. Overall, this work provides compelling support for dietary intervention or pharmacologic therapy directed at downstream PGE2 signaling as approaches to reduce HO in at-risk patients.
Authors
Peyton L. Carpen, Matthew B. Greenblatt
Abstract
Fibrosis is driven by the activation of quiescent fibroblasts into contractile, matrix-secreting myofibroblasts, a transition governed jointly by biochemical signals and by the mechanical properties of the ECM. How the physical stiffness of tissue is converted into a durable transcriptional cell fate decision has remained poorly understood. In this issue of the JCI, Kadri et al. used global phosphoproteomic profiling of primary human lung fibroblasts across a defined stiffness gradient to identify phosphorylation of NFATC4 at residues S213/S217 as a mechanosensitive switch that is both necessary and sufficient for the fibroblast-to-myofibroblast transition. They validated these predictions in an independent transcriptomic dataset from patients with idiopathic pulmonary fibrosis, showing that NFATC4 expression increased with disease severity. Prior work has implicated NFATC4 activation in cardiac and hepatic fibrosis, suggesting that this single modification may serve as a convergence point for mechanical and cytokine signals across fibrotic diseases.
Authors
Rebecca Shelley Frabotta, Purushothama Rao Tata
Abstract
Fibrosis remains a major driver of organ dysfunction, yet the metabolic programs that sustain extracellular matrix production are incompletely understood. In this issue of the JCI, Takizawa and colleagues identified branched-chain amino acid transaminase 1 (BCAT1) as a crucial metabolic regulator of fibroblast activation and fibrosis in a model of cardiac fibrosis. Their observations were corroborated by analyses of datasets from patients with heart failure with preserved ejection fraction and metabolic dysfunction–associated steatohepatitis. They report that by coupling mechanical and TGF-β signaling to a proline biosynthesis and utilization program, BCAT1 enhanced collagen production in activated cardiac fibroblasts. These findings place branched-chain amino acid metabolism as a pivotal contributor to fibroblast activation and highlight BCAT1 as a promising therapeutic target for fibrotic disease.
Authors
Marco Ronfini, John W. Elrod
Abstract
Monocytes and macrophages promote tissue repair following myocardial infarction, but the mechanisms tuning their effector functions remain elusive. While macrophages are essential in clearing debris and resolving inflammation, they can also contribute to uncontrolled inflammation and provoke additional damage. Thus, factors that influence macrophage differentiation trajectories and phenotypes play an important role in cardiac repair outcomes. By combining genetic lineage tracing with cell-specific targeting, the study from Koenig et al. sheds light on key signaling events that shape monocyte fate decisions in the injured myocardium, establishing a differentiation hierarchy among monocyte-macrophage subsets. The findings also reveal that macrophages with an IFN response signature give rise to MHCIIhi macrophages, which, in turn, contribute to regulatory T cell generation and cardioprotection. This work underscores the importance of understanding cardiac macrophage phenotypic plasticity within a broader framework of lineage relationships.
Authors
Ecem Tugba Sakalli, Giuseppe Rizzo, Alma Zernecke, Gustavo Campos Ramos
Abstract
Menopause may have important consequences for gut barrier health. The roles of estradiol and progesterone in immune and mucosal barrier homeostasis have been well studied in the female reproductive tract. However, few human studies have described these hormones’ corresponding regulation in the gastrointestinal tract or how the menopausal transition affects gut barrier integrity. In this issue of the JCI, Shieh et al. report that markers of gut epithelial barrier dysfunction and microbial translocation–related immune activation increased across the menopause transition in a longitudinal study of healthy women. These findings suggest that ovarian aging may contribute to gut barrier dysfunction in midlife women and highlight new questions about clinical consequences and potential interventions.
Authors
Brandilyn A. Peters
Abstract
Monoclonal antibodies (mAbs) targeting Plasmodium falciparum epitopes aim to address gaps in malaria prevention, with potential to profoundly impact high-risk populations. In this issue of the JCI, Tran et al. performed pharmacokinetic and pharmacodynamic analyses on the mAb CIS43LS, which targets a unique conserved hinge region on the sporozoite protein CSP and previously demonstrated a high level of durable protection in controlled human malaria infections. Their findings establish a solid benchmark for mAb protection, demonstrating 80% protection from liver-stage invasion for 4–6 months. A clinical correlate of protection was estimated at antibody levels over 64 μg/mL. Successful protection could also be achieved from subcutaneous injections requiring lower doses. While efficacy of individual mAbs is more straightforward to demonstrate, exploring combination approaches targeting variable regions and diverse effector functions seems prudent to address the problem of evolving microbial pathogens. Combining both mAbs and long-acting malaria drugs may improve efficacy and reduce resistance.
Authors
David J. Sullivan
Abstract
The ability of cancer cells to transition between epithelial and mesenchymal states, a process known as epithelial-to-mesenchymal transition (EMT), is a key driver of cancer metastasis and therapy resistance. While ataxia telangiectasia and Rad3-related (ATR) kinase was originally characterized as a responder to DNA damage and replication stress, recent discoveries implicate a critical role for ATR in EMT and metastasis. Two pivotal studies published in this issue of JCI provide key insights into how ATR intersects with EMT transcriptional reprogramming. Patel et al. demonstrated that ATR prevented R-loop accumulation at EMT-related gene loci, thereby facilitating the transcriptional reprogramming necessary for EMT as well as tumor growth and metastasis. Tu et al. further uncovered a role for ATR in ECM stiffness–induced EMT, which was associated with an immunosuppressive tumor microenvironment. Together, these studies highlight important therapeutic implications for ATR targeting in the context of metastasis and therapy resistance.
Authors
Aida Mestre-Farrera, Zhimin Hu, Jing Yang
Abstract
Pancreatic β cells regulate glucose homeostasis through insulin secretion, but nutrient overload and genetic defects can trigger ER stress and apoptosis, contributing to type 2 diabetes. Within β cells, the kinases PERK, IRE1α, and ATF6 initiate the unfolded protein response (UPR) as a result of ER stress, a process that is constitutively suppressed under nonstress conditions by GRP78 binding to these proteins. To gain insight into the mechanisms of β cell death upon dysregulated ER stress, Sharma et al. used β cell–specific GRP78 knockout models, revealing that hyperactivation of the UPR promoted β cell death primarily through the IRE1α/JNK/p53 signaling pathway. Pharmacological inhibition of JNK improved β cell survival, increased insulin levels, and lowered blood glucose in multiple diabetic mouse models. These findings highlight JNK signaling as a promising therapeutic target for preserving β cell function.
Authors
Jonathan M. Palozzi, Pere Puigserver
Abstract
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 lymphatic development and drainage promote valve inflammation through reduced ZFP36-mediated antiinflammatory signaling, whereas restoration of lymphatic function or pharmacological activation of ZFP36 with the FDA-approved drug FTY720 ameliorates disease progression. These findings establish lymphatic vessels as critical regulators of mitral valve homeostasis and support exploration of lymphatic-targeted therapeutic opportunities for MFS-associated valvular disease.
Authors
Yanna Tian, Kathleen M. Caron
Abstract
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. challenge this binary classification using cardiac-specific strategies to expand either em-CM or mo-CM populations. As expected, mice with cardiac-specific mo-CM expansion exhibited adverse outcomes following transverse aortic constriction (TAC). Surprisingly, mice with expanded em-CMs also showed a marked decline in cardiac function after TAC, which was associated with an unexpected interaction with mo-CMs. This deterioration was temporally regulated, occurring only if em-CMs were expanded before TAC induction. Together, these findings suggest that simplistic classification of CMs as either beneficial or harmful underestimates their complex roles in cardiac pathology, highlighting the need to reassess current views of macrophage function in heart injury.
Authors
Janmes Karunamurthy, Ziyi Li, Ajitha Thanabalasuriar
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