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Regulation of the Pro-fibrotic and Pro-tumorigenic ROBO1 by YAP and LHX2 in Metabolic Dysfunction-Associated Steatohepatitis

Award Number: R01DK149400
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/10/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2030

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Regulation of the Pro-fibrotic and Pro-tumorigenic ROBO1 by YAP and LHX2 in Metabolic Dysfunction-Associated Steatohepatitis - Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a spectrum of liver pathologies, from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), progressing to fibrosis, cirrhosis with angiogenesis and ductular reaction, and ultimately liver failure and/or hepatocellular carcinoma. This study aims to identify molecular targets and pathways that promote liver regeneration while reducing fibrosis. We and others have demonstrated that aberrant cell–cell and cell–matrix interactions drive hepatic stellate cell (HSC) activation. Notably, Roundabout receptor 1 (ROBO1) and its ligand SLIT2 promote liver fibrosis through crosstalk with connective tissue growth factor (CTGF), a matricellular protein that engages several integrin subtypes, including integrin αvβ1. Our preliminary data show that the ectodomain of ROBO1 contains an RGD (arginylglycylaspartic acid) motif critical for binding integrin αvβ1. Mutation of this motif abolishes ROBO1–αvβ1 interaction and reduces HSC activation in a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) model of MASH. Concurrently, Yes-associated protein (YAP)—a nuclear effector of mechanotransduction and ECM stiffness—induces profibrotic genes such as Ctgf and Robo1 in myofibroblasts. These changes correlate with a reduction of the transcriptional repressor LIM homeobox 2 (LHX2), an antifibrotic factor that promotes hepatocyte growth factor (HGF) expression in quiescent HSCs. Thus, we hypothesize that ROBO1, upregulated by YAP activation and LHX2 loss, cooperates with integrin αvβ1 to amplify PI3K/Akt/β-catenin signaling upon SLIT2 and CTGF stimulation in activated HSCs, thereby promoting fibrosis in MASH. In Aim 1, we will test whether ROBO1 synergizes with integrin αvβ1 to promote fibrogenesis in MASH. Using the Gubra Amylin NASH (GAN) diet model—which closely mirrors the metabolic and fibrotic features of human MASLD—we will determine whether HSC-specific deletion of Robo1 disrupts integrin αvβ1 signaling and reduces fibrosis. Gain- and loss-of-function constructs will be used to evaluate how RGD recognition modulates integrin signaling. We will also engineer chimeric antigen receptor (CAR) immune cells to selectively ablate ROBO1⁺ HSCs in human precision-cut liver slices (PCLS), liver organoids, and GAN- induced rat MASH models. In Aim 2, we will investigate the regulation of ROBO1 by YAP and LHX2 using genetically modified models and newly developed inhibitors that induce YAP proteasomal degradation. This study will validate the SLIT2–ROBO1 axis as a profibrotic pathway and uncover therapeutic vulnerabilities involving ROBO1–integrin αvβ1 cooperation, YAP activation, and LHX2 suppression. Together, these findings will provide a foundation for novel antifibrotic strategies, including ROBO1-targeted CAR therapies and first-in- class YAP degraders. Ultimately, this work addresses a critical unmet need in MASH by targeting fibrosis—the strongest predictor of liver-related mortality—and may significantly reduce the burden of chronic liver disease.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $651,222 )
2026	2026	THE ADMINISTRATORS OF TULANE EDUCATIONAL FUND	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/3/2026	NEW	$651,222
														Subtotal = $651,222

Grand Total All Awards = $651,222

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Regulation of the Pro-fibrotic and Pro-tumorigenic ROBO1 by YAP and LHX2 in Metabolic Dysfunction-Associated Steatohepatitis

Award Number: R01DK149400

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/10/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2030

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