Researchers at the University of Houston, working with collaborators at Baylor College of Medicine and The University of Texas MD Anderson Cancer Center, have identified a mechanism that identifies epithelial cell stress as a one of the main drivers of Crohn’s disease, a finding that runs counter to much current thinking of Crohn’s disease as immune-mediated and instead frames it as a failure of within the intestinal barrier. The study, published in Gastro Hep Advances, shows that chronic integrated stress response (ISR) activation and a related cell death pathway, necroptosis, form a feedback loop that damages intestinal epithelial cells and prevents cell regeneration leading to sustained inflammation.
“It’s a paradigm shift from the way we’ve thought about the disease,” said senior author Seema Khurana, PhD, a professor of biology and biochemistry at the University of Houston. “Existing therapies primarily manage symptoms because we don’t know what causes the disease. We believe our research brings us closer to identifying those drivers.”
Crohn’s disease is typically treated with anti-inflammatory therapies aimed at suppressing immune activity, but only a minority of patients have long lasting benefits. This current study may help explain why anti-inflammatories only have limited benefits by showing that intestinal barrier dysfunction is not simply a consequence of inflammation but is a factor in disease development.
For their research, the team sought to discover how stress signaling within certain epithelial cells contribute to disease progression. The ISR is a conserved cellular pathway that helps cells respond to stress by temporarily reducing protein production and activating processes that restore cellular balance, including stress-response gene expression, protein quality control, and metabolic adaptation. While short-term ISR activation is a temporary response to cellular stress, the researchers found that in Crohn’s disease, ISR signaling becomes chronically activated.
“Our results identify ISR activation as a unifying hallmark of epithelial stress in CD, regardless of whether the initiating insult is intrinsic (loss of villin-1/gelsolin) or extrinsic (TNF-α dysregulation),” the researchers wrote.
The result of this chronic ISR activation is that instead of helping epithelial cells become healthy, they are instead kept in a dysfunctional state. This leads to mitochondrial stress and triggers necroptosis, a form of programmed cell death that releases inflammatory signals. The combination of ongoing stress signaling and cell death prevents epithelial regeneration and weakens the intestinal barrier, allowing microbes to infiltration tissue in the intestine further increasing inflammation.
Prior studies have focused on this form of dysfunction to Crohn’s disease, but ISR activation had not been clearly characterized as a central driver of disease development. To address this, the team used a number of different models of Crohn’s disease, including genetically engineered mice with epithelial-specific ISR activation, mice with chronic inflammation driven by TNF-α dysregulation, and patient-derived intestinal organoids. The organoids allowed the researchers to directly study human epithelial responses.
The resulting data showed that for all the models, the same pattern of chronic ISR activation, increased necroptosis, impaired epithelial survival, and failure of regenerative growth emerged.
To begin finding potential therapeutic approaches based on these new findings, the investigators then tested whether blocking these pathways could reverse intestinal damage. Using both experimental inhibitors and two FDA-approved cancer drugs, pazopanib and ponatinib, repurposed at low concentrations, they were able to suppress ISR signaling and necroptosis. This restored epithelial cell survival, improved regeneration, and reestablished barrier integrity.
“A major advance of this work is the demonstration that pharmacologic inhibition of ISR or necroptosis restores epithelial homeostasis by promoting regenerative growth of the epithelium in both murine and human models of CD,” the researchers wrote.
If additional studies can establish ISR inhibition as safe and effective for human use, this research could be the beginning of a shift in how Crohn’s disease is treated. Instead of focusing only on controlling inflammation, a new class of treatments could aim to repair the epithelial barrier directly. This approach aligns with emerging evidence that permeability barrier healing is a stronger predictor of long-term remission than traditional measures such as mucosal healing.
Further, because both pazopanib and ponatinib are already approved drugs that are known to be safe and have well characterized pharmacology profiles, the path to these new treatments could be on a fast track.
“If you had to start from scratch to identify and develop a drug, it takes 10 to 15 years and can cost between $1 billion to $2 billion,” Khurana said. “For a patient who is suffering from chronic Crohn’s disease, they’re looking for some immediate relief. Our goal was to make our findings much more translatable to real patients.”
Beyond drug development, the study points to new opportunities for improving clinical care. Biomarkers of ISR activation, such as phosphorylated eIF2α or RIPK3 expression, could help identify patients with barrier dysfunction and guide treatment decisions. Patient-derived organoid systems may also enable personalized testing of therapeutic responses before treatment.
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