Introduction

Gastric chief cells can re-enter the cell cycle after injury through paligenosis, a conserved regenerative program regulated by mTORC1. This process involves (1) cellular degradation, (2) induction of progenitor genes (spasmolytic polypeptide-expressing metaplasia, SPEM), and (3) cell cycle re-entry. Dysregulated paligenosis contributes to gastric cancer, but mechanisms governing this reprogramming remain incompletely understood. Here, we investigated the role and regulation of YAP1, a key effector of the Hippo pathway, during paligenosis.

Aims & Methods

Our objectives were to determine whether YAP1 is activated during paligenosis, define its role, and identify upstream regulators. Using a mouse model of injury-induced paligenosis (via high-dose tamoxifen, HDTAM, intraperitoneal injection), we analyzed YAP1 activation and Hippo pathway dynamics via proteomics, single-cell RNA sequencing, western blot, immunohistochemistry, and immunofluorescence. To dissect upstream signaling, we employed a series of genetically engineered mouse models targeting Hippo pathway components.

Results

YAP1 is rapidly activated (via dephosphorylation) during the early stage of paligenosis. Functional assays revealed that YAP1 (and its paralog, TAZ) are necessary and sufficient to drive chief cell reprogramming. Among upstream kinases, only STK38 activity mirrored YAP1 activation patterns. STK38 is essential for YAP1 activation and is degraded via autophagy during transition to stage 2. Notably, STK38 harbors a UFM1/LC3-interacting region (LIR) domain and is targeted to autophagosomes. We found that MIST1 induces UFM1, which protects STK38 from autophagic degradation. In Mist1^−/− mice, reduced UFM1 correlates with heightened basal autophagy, STK38 loss, and constitutive YAP1 activation. Furthermore, STK38 interacts with NF2, similar to canonical Hippo kinases, modulating YAP1 regulation.

Conclusion

We identify a novel MIST1–UFM1–STK38 axis that regulates YAP1 activity in an autophagy-dependent manner during paligenosis. STK38 acts as a non-canonical Hippo kinase whose stability dictates YAP1 activation. These findings uncover new layers of Hippo pathway regulation and highlight the dynamic control of YAP1 during gastric epithelial regeneration.

Introduction

Upper GI involvement in Crohn’s disease (CD) is thought to occur in 13% to 15% of cases. However, despite expansion of the therapeutic armamentarium for CD over the last 30 years, there continues to be minimal data on optimal therapeutic strategies for upper GI CD. This knowledge gap presents major clinical challenges in managing this subset of patients.

Aims & Methods

We conducted an extensive systematic review using multiple databases investigating pharmacological or dietary interventions for patients with upper GI CD. We included fully published, English-language studies that compared at least two active interventions with a placebo from 1990 to 2025. Due to the lack of a standardized definition for “upper GI” CD, we included studies that reported data on CD affecting the esophagus to the jejunum. We excluded studies that included <10 upper GI CD patients, reported data for “small bowel CD” in general or limited to ileal CD, or did not report data separately for upper GI CD. There is no age limitation.

Results

Among 1206 citations, 14 observational studies (11 retrospective, 3 prospective) and 1 post hoc of an RCT met our inclusion criteria, amounting to 487 patients with UGI CD. Majority of patients had concomitant ileocolonic involvement. Five studies with 137 patients had esophageal CD. Follow-up ranged from 1 to 28 years. Interventions and reported outcomes varied. Steroids (mainly prednisone) and anti-TNF, either alone or in combination, showed the highest rates of success for clinical improvement, endoscopic healing and histologic remission for upper GI CD compared to other therapies. Other therapies used, alone or in combination, were EEN, PPI, H2RA, immunomodulators (azathioprine, 6-mercaptopurine), 5-ASA, anti-integrins, and anti-IL 12/23, showing moderate to minimal improvement in clinical or endoscopic response and remission. (Table)

Conclusion

Our comprehensive literature search of comparative studies highlights an almost void of evidence to inform therapeutic strategies in upper GI CD. Steroids and anti-TNF showed the best outcomes, but only from small observational, uncontrolled studies. Data for biologics and advanced therapies remain limited highlighting a large unmet need.

Disclosure

Financial Disclosures:
MC: none.
DA: none.
YY: has received consulting fees from Alimentiv.
VJ: has received consulting/advisory board fees from AbbVie, Alimentiv, Anaptyis Bio, Arena pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, Avoro Capital, Bristol Myers Squibb, Celltrion, Eli Lilly, Endpoint Health, Enthera, Ensho, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, Gilde Healthcare, GlaxoSmithKline, Genentech, Gilead, Innomar, JAMP, Janssen, Merck, Metacrine, Mylan, MRM Health, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus Biosciences, Reistone Biopharma, Roche, Roivant, Sandoz, Second Genome, Sorriso, Synedgen, Takeda, TD Securities, Teva, Topivert, Ventyx, Vividion; speaker’s fees from, Abbvie, Ferring, Bristol Myers Squibb, Galapagos, Janssen Pfizer Shire, Takeda, Tillotts, Fresenius Kabi
RS: has received consulting fees from AbbVie, Alimentiv and Takeda.