Aug 2026· Frontiers in Physiology· 0 citations· 143 references
TL;DR
Evidence is synthesized from genetically engineered mouse models that enhanced trypsinogen autoactivation alone is sufficient for spontaneous disease, that NF-κB-driven inflammation can be initiated independently of trypsin, and that loss of autophagy alone disrupts acinar homeostasis, which reframe pancreatitis as a network pathophysiology with two coupled layers.
Abstract
Pancreatitis remains a common gastrointestinal disease with no mechanism-specific therapy. Its pathogenesis was long explained by the autodigestion hypothesis: a single linear cascade initiated by premature intra-acinar trypsinogen activation. This trypsin-centric view cannot account for the amplification of inflammation, the switching of cell-death modality, the acute-to-chronic transition, organ failure, or the chronic pancreatitis caused by protein-misfolding genes that act outside the protease system. Here we synthesize evidence from genetically engineered mouse models (GEMMs); their loss- and gain-of-function designs, spanning global and conditional knockouts, knock-ins, and CRISPR/Cas9 editing, can separate molecular events that are necessary, sufficient, or merely correlated. These models show, for example, that enhanced trypsinogen autoactivation alone is sufficient for spontaneous disease, that NF-κB-driven inflammation can be initiated independently of trypsin, and that loss of autophagy alone disrupts acinar homeostasis. On this basis we reframe pancreatitis as a network pathophysiology with two coupled layers. First, acinar homeostasis is maintained by several semi-independent control modules (digestive-enzyme safety, endoplasmic reticulum protein quality control, the autophagy–lysosome system, the calcium–mitochondria axis, and NF-κB signaling), so that disease can be initiated at any of several independent nodes. Second, the injured acinar cell dies through an interconnected, switchable network of regulated cell death (apoptosis, necroptosis, pyroptosis, ferroptosis, and PANoptosis), sharing nodes such as caspase-8, RIPK3, and GPX4, whose configuration, more than the initiating trigger, determines severity. This framework recasts the heterogeneity of human pancreatitis as different entry points into one network and argues for therapies directed at shared nodes rather than single pathways.
The Hippo pathway is an evolutionarily conserved regulator of growth, regeneration, and organ homeostasis, and while its dysregulation is well established in cancer, the effects of inhibiting this pathway on normal tissues are less understood. Here we have systematically investigated the impact of Hippo pathway inhibition by comparing pharmacologic perturbation using a covalent small-molecule TEAD inhibitor (TEADi CMPD1, also known as GNE-8025) with genetic suppression of YAP/TAZ. We identified three key target organs that consistently emerged upon TEAD inhibition: the kidney, as well as the pancreas, and thymus. Across models, both perturbations led to comparable disease phenotypes in these organs, including tubular degeneration in the kidney, acinar atrophy in the pancreas, and lymphoid depletion in the thymus. However, the extent of damage was more pronounced in mice treated with the small-molecule inhibitor, highlighting potential dose and compound specific effects while remaining broadly consistent with the phenotypes observed upon genetic ablation of YAP/TAZ. This highlights the key role of evaluating both genetic and pharmacological perturbations to characterize the phenotypes and potential toxicities when modulating novel targets in oncology. To further investigate the mechanisms underlying pan-TEAD inhibition and kidney related adverse effects, we further characterized this class effect through a comprehensive transcriptomic analysis of the kidney to map the pathways involved in renal response. Significance Understanding on target toxicities is critical for the safe clinical development of TEAD inhibitors. Here, by integrating pharmacologic TEAD inhibition with genetic suppression by developing a mouse model that characterizes systemic, inducible knockdown of YAP/TAZ, we provide a systematic framework to define the Hippo pathway liabilities in vivo. We identify kidney, pancreas, and thymus as conserved target organs with concomitant phenotypes across both genetic and pharmacological methods, establishing these as pathway driven effects. Importantly, we uncover dose dependent and partially irreversible injury, particularly in kidney and pancreas, alongside mechanistic insight linking TEAD inhibition to aldosterone signaling disruption in kidney. These findings highlight the importance of strategies to identify monitorable, manageable adverse effect to guide clinical translation of TEAD targeting strategies.
Sayantanee Paul, Michelle Lepherd, Thijs J. Hagenbeek et al.· bioRxiv· 0 citations
Introduction Parkinson’s disease (PD) is increasingly recognized as a neurological disorder characterized not only by neurodegeneration but also by chronic immune dysregulation across the lifespan. Although the initiating events underlying PD remain unclear, accumulating evidence suggests that inflammatory processes may contribute to disease susceptibility and progression. Mutations in leucine-rich repeat kinase 2 (LRRK2), particularly the gain-of-function G2019S variant, represent the common genetic cause of familial PD and have been implicated in immune regulation and infection susceptibility. To date, most research has focused on the effect of LRRK2 mutation in neurons and the contributions of G2019S-mediated kinase activity to neuronal toxicity, leaving the role of G2019S-mediated kinase activity in immune cell homeostasis and its contribution to PD pathogenesis largely unresolved. Methods Here, we used murine overexpression models of wildtype and G2019S variant of mouse Lrrk2 to examine how Lrrk2 G2019S shapes host defense across viral and bacterial infection models. We tested systemic sepsis and Escherichia coli infection to examine bacterial clearance. We followed up by testing macrophage responses to intracellular (Listeria monocytogenes) or primarily extracellular (Pseudomonas aeruginosa) bacteria. Finally, tested antibody-mediated immunity using influenza and cytotoxic T cell-mediated immunity using lymphocytic choriomeningitis virus (LCMV) infection. Results We found that Lrrk2 G2019S overexpression enhanced survival and bacterial clearance during P. aeruginosa lung infection, whereas the same genotype worsened outcomes in polymicrobial sepsis, with increased mortality, pulmonary myeloid infiltration and a hematopoietic cell-intrinsic phenotype. During L. monocytogenes infection, Lrrk2 G2019S selectively reduced non-classical monocytes without altering disease progression. In influenza and LCMV infection, G2019S altered antigen-specific CD8+ T cell distribution without major changes in cell memory responses clinical severity. Discussion Together, these data show that Lrrk2 G2019S selectively reprograms innate and adaptive immunity in a pathogen- and tissue-dependent manner, uncoupling inflammatory magnitude from effective host defense. These results and previous work support a model in which the G2019S LRRK2 variant contributes to maladaptive inflammatory responses to specific infection challenges, providing insight into how lifetime immune perturbations may intersect with genetic susceptibility to influence lifetime infection risk.
Andrea R. Merchak, Mary K. Herrick, M. Houser et al.· Frontiers in Cellular Neuros...· 0 citations
Kidney fibrosis is the final common pathological pathway through which chronic kidney disease progresses to end-stage kidney disease, yet therapies designed specifically to interrupt the core fibrotic process in the kidney are still lacking. This unmet need reflects the biological heterogeneity of kidney fibrosis, the context dependent interplay among inflammatory, metabolic and mechanical signals, and the limited translational value of many conventional preclinical models. The mechanistic landscape has also broadened considerably beyond canonical transforming growth factor-β signaling, now encompassing immune-stromal crosstalk, metabolic rewiring, mechanotransduction, epigenetic reprogramming and extracellular vesicle-mediated communication. These developments have brought several druggable nodes into view and may support more selective and durable antifibrotic interventions. At the same time, translational platforms including artificial intelligence-assisted in silico screening, patient-derived kidney organoids, bioengineered tissue systems and refined animal models are changing how targets are discovered and pharmacologically validated. In this review, we examine emerging mechanisms that govern kidney fibrogenesis, with emphasis on therapeutic tractability, and consider how experimental models can improve target prioritization and drug development. We also summarize repurposed drugs, pathway-targeted agents, receptor-directed strategies and cell-based approaches under preclinical or clinical evaluation. We close by discussing key barriers to clinical translation, including disease heterogeneity, inadequate biomarkers and the need to balance antifibrotic efficacy with renal safety. A pharmacology driven framework that links mechanism, model and patient stratification could help accelerate precision antifibrotic therapy for kidney disease.
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Background:
Cholangiocarcinoma (CCA) is a lethal malignancy with limited understanding of its early developmental mechanisms. A significant subset of CCA harbors gain-of-function mutations in
IDH1
(e.g., R132C), which promotes accumulation of the oncometabolite 2-hydroxyglutarate (2-HG). A major barrier in dissecting early events is the lack of models that faithfully recapitulate human physiology. Patient-derived organoids (PDOs) retain the genetic and phenotypic diversity of the original tissue. Base editing now enables the introduction of specific nucleotide mutations into physiologically relevant models to study causal driver events. However, the oncogenic impact of IDH1 mutations on normal and pre-diseased cholangiocytes, and their synergy with factors like bile acids, are poorly defined.
Methods:
Normal and dilated cholangiocyte organoids were derived from clinical specimens. Cytosine base editing installed the IDH1 R132C mutation. Phenotypes (proliferation, invasion, CEA/CA19-9 secretion) and 2-HG levels were assessed, with/without bile acid challenge. Integrated transcriptomics and metabolomics delineated underlying reprogramming.
Results:
Introduction of the
IDH1
R132C mutation into both normal and dilated cholangiocyte organoids induced a pro-oncogenic phenotype, including enhanced proliferation, invasion, and secretion of CEA/CA19-9, concomitant with 2-HG accumulation. Mechanistically, multi-omics analysis revealed that IDH1 R132C, particularly in dilated cholangiocytes, drives a transcriptional program characteristic of early biliary transformation, involving dysregulation of pathways governing cell fate (e.g., Hippo/YAP suppression) and metabolism (e.g., upregulated glutaminolysis). Crucially, bile acids acted as a potent synergistic cofactor, amplifying phenotypes and rewiring the metabolic network to create a dependency on specific biosynthetic pathways. This combination effectively locked organoids into a proliferative, precursor-like state.
Conclusions:
We have established a novel, physiologically relevant in vitro model that recapitulates the synergistic oncogenesis driven by
IDH1
mutation and microenvironmental stress in early CCA. Our study moves beyond phenomenology to identify the critical early molecular and metabolic nodes activated during this transformation. Importantly, by targeting a key identified metabolic vulnerability (e.g., with a glutaminase inhibitor or a mutant IDH1 inhibitor), we were able to significantly attenuate the observed hyperproliferative and invasive phenotypes, and reduce tumor marker secretion. This work provides a preclinical platform for identifying and testing interceptive strategies aimed at reversing or halting early cholangiocarcinogenesis in high-risk settings.
Ziye Chen, Qingru Song, Jinxin Wang et al.· Journal of Clinical Oncology· 0 citations
Genome-wide CRISPR screens have systematically identified genes required for cancer cell survival, yet these studies are typically performed under standardized conditions that do not fully recapitulate the physiological stresses encountered within the tumor microenvironment. In a recent issue of Nature Genetics, Cheruiyot and colleagues perform genome-wide loss-of-function screens under inflammatory conditions induced by interferon-β (IFN-β), interferon-γ (IFN-γ), and tumor necrosis factor (TNF), revealing that distinct cytokines impose different genetic requirements for tumor cell survival. The study shows that inflammatory signaling reshapes genetic dependency landscape in a cytokine-specific manner. Mechanistic analyses identify the glycosylphosphatidylinositol (GPI) transamidase complex and FITM2 as representative examples of genes that become selectively required under inflammatory stress by maintaining membrane protein maturation, endoplasmic reticulum homeostasis, and resistance to oxidative stress. These findings broaden our understanding of how inflammatory cytokines influence tumor cell biology beyond transcriptional regulation and immune recognition. More broadly, the study highlights the value of incorporating physiologically relevant conditions into functional genetic screens, suggesting that conventional dependency maps capture only part of the genetic requirements for tumor survival. Applying similar approaches to other microenvironmental stresses-including hypoxia, metabolic competition, extracellular matrix remodeling, and stromal signaling-may uncover additional therapeutic opportunities for cancer immunotherapy.
Zihan Ning, Guangchuan Wang· Cancer Research· 0 citations
Summary KAT8 (MOF/MYST1) is a core histone acetyltransferase of the MYST family. Beyond its canonical H4K16ac activity, KAT8 catalyzes diverse acylations and regulates stem cell biology, DNA repair, metabolism, and immunity. This review systematically integrates KAT8’s regulatory networks across physiology and disease. We decipher the molecular basis of its context-dependent “double-edged sword” role in cancer, acting predominantly as an oncoprotein yet exhibiting tumor-suppressive functions under specific conditions. We evaluate current KAT8 inhibitor development, from early non-selective compounds to selective leads, and highlight persistent translational hurdles including insufficient specificity and limited in vivo efficacy. This work provides a comprehensive framework that clarifies recent controversies—such as whether H4K16ac primarily governs transcription or replication timing, and which KAT8-containing complex catalyzes, which acetylation mark—and establishes a rationale for future precision-targeting strategies and biomarker development grounded in KAT8 functional heterogeneity.
A new method for surgically removing training examples from a model reveals that as datasets grow, the link between what a model learns and what it produces dissolves.
MIT News · Artificial Intelligence· news.mit.eduAug 17, 2026
