---
title: "Brain-penetrant CHI3L1 inhibitor DELC2 modulates neuroinflammation in Alzheimer’s models"
id: "biorxiv-1-discovery-of-a-brain-penetrant-chi3l1-inhibitor-as-an-oral-modulator-of"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-1-discovery-of-a-brain-penetrant-chi3l1-inhibitor-as-an-oral-modulator-of"
content_type: "clinical_feed_article"
specialty: "Neurology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.10.15.759511v1?rss=1"
published_at: "2026-10-21T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Brain-penetrant CHI3L1 inhibitor DELC2 modulates neuroinflammation in Alzheimer’s models
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-1-discovery-of-a-brain-penetrant-chi3l1-inhibitor-as-an-oral-modulator-of
- **Specialty:** [Neurology](https://medichelpline.com/clinical-feed/neurology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.10.15.759511v1?rss=1)
- **Published At:** 2026-10-21T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- Investigators screened a 4.2‑billion‑compound DNA‑encoded library and identified DELC2 as a small‑molecule modulator of **CHI3L1**. - Biophysical and crystallographic data showed DELC2 binds the CHI3L1 glycan‑recognition groove in an aromatic‑hydrophobic pocket centered on Trp99 and Trp352. - DELC2 inhibited **CHI3L1–RAGE** association and suppressed CHI3L1‑driven inflammatory signaling in cellular assays. - In primary glial cultures, DELC2 reduced Gal‑3–positive microglia and restored **amyloid‑β** uptake impaired by CHI3L1. - Human cerebrospinal fluid (CSF) samples in the report showed elevated CHI3L1 in Alzheimer’s disease and a correlation with astrocytic NF‑κB activation. - DELC2 phenocopied the effects of CHI3L1 immunodepletion; conversely, CHI3L1 add‑back reinstated inflammatory and amyloid‑handling defects. - Oral administration of DELC2 delivered sustained unbound brain exposure in 5xFAD mice, improved cognitive performance, reduced multiple **amyloid‑β** species, and attenuated astrocytic and microglial inflammatory programs. - The authors position the CHI3L1 glycan‑recognition groove as a druggable regulator of RAGE‑associated glial dysfunction and describe DELC2 as a chemical scaffold for CHI3L1‑directed therapy in Alzheimer’s disease. - The source is a preprint and has not undergone peer review; the manuscript did not report clinical dosing regimens or human therapeutic data.
## Clinical Analysis & Structured Key Points
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Saurabh Upadhyay 1 Columbia University Irving Medical Center; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Saurabh%2BUpadhyay%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Upadhyay%20S&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ASaurabh%2BUpadhyay%2B) Longfei Zhang 2 Weill Cornell Medicine; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Longfei%2BZhang%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Zhang%20L&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ALongfei%2BZhang%2B) Baljit Kaur 1 Columbia University Irving Medical Center; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Baljit%2BKaur%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Kaur%20B&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ABaljit%2BKaur%2B) Laura Calvo-Barreiro 2 Weill Cornell Medicine; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Laura%2BCalvo-Barreiro%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Calvo-Barreiro%20L&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ALaura%2BCalvo-Barreiro%2B) Marianna Teplova 3 Memorial Sloan Kettering Cancer Center * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Marianna%2BTeplova%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Teplova%20M&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AMarianna%2BTeplova%2B) Moustafa Gabr 1 Columbia University Irving Medical Center; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Moustafa%2BGabr%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Gabr%20M&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AMoustafa%2BGabr%2B) * For correspondence: mg5065@cumc.columbia.edu * [Abstract](https://www.biorxiv.org/content/10.64898/2026.10.15.759511v1)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_art/node:5890993/1) * [Info/History](https://www.biorxiv.org/content/10.64898/2026.10.15.759511v1.article-info)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_info/node:5890993/1) * [Metrics](https://www.biorxiv.org/content/10.64898/2026.10.15.759511v1.article-metrics)[](https://www.biorxiv.org/panels_ajax_tab/article_tab_metrics/node:5890993/1) * [Supplementary material](https://www.biorxiv.org/content/10.64898/2026.10.15.759511v1.supplementary-material)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_data/node:5890993/1) * [ Preview PDF](https://www.biorxiv.org/content/10.64898/2026.10.15.759511v1.full.pdf+html)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_pdf/node:5890993/1) ![Loading](https://www.biorxiv.org/sites/all/modules/contrib/panels_ajax_tab/images/loading.gif) ## Abstract Chitinase-3-like protein 1 (CHI3L1) is elevated in Alzheimers disease (AD), but its role in glial dysfunction and therapeutic tractability remain unclear. Here, screening a 4.2-billion-compound DNA-encoded library identified DELC2, a brain-penetrant CHI3L1 modulator. Biophysical and crystallographic studies showed that DELC2 binds the CHI3L1 glycan-recognition groove within an aromatic-hydrophobic pocket centered on Trp99 and Trp352. DELC2 inhibited CHI3L1-RAGE association, suppressed CHI3L1-induced inflammatory signaling, reduced Gal-3-positive microglia, and restored amyloid-β uptake in glial cultures. In human cerebrospinal fluid, CHI3L1 was elevated in AD and correlated with astrocytic NF-κB activation. DELC2 phenocopied CHI3L1 immunodepletion, whereas CHI3L1 add-back restored inflammatory and amyloid-β-handling defects. Oral DELC2 achieved sustained unbound brain exposure in 5xFAD mice, improved cognitive performance, reduced multiple amyloid-β species, and attenuated astrocytic and microglial inflammatory programs. These findings establish the CHI3L1 glycan-recognition groove as a druggable regulator of RAGE-associated glial dysfunction and identify DELC2 as a chemical scaffold for CHI3L1-directed therapy in AD. ### Competing Interest Statement The authors have declared no competing interest. Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. bioRxiv and medRxiv thank the following for their generous financial support: > The Chan Zuckerberg Initiative, Cold Spring Harbor Laboratory, the Sergey Brin Family Foundation, California Institute of Technology, Centre National de la Recherche Scientifique, Fred Hutchinson Cancer Center, Imperial College London, Massachusetts Institute of Technology, Stanford University, The University of Edinburgh, University of Washington, and Vrije Universiteit Amsterdam. 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[ Download PDF](https://www.biorxiv.org/content/10.64898/2026.10.15.759511v1.full.pdf) Print/Save Options [Download PDF](https://www.biorxiv.org/content/biorxiv/early/2026/10/21/2026.10.15.759511.full.pdf)Full Text & In-line FiguresXML [More Info](https://www.biorxiv.org/about/FAQ#PrintOptions "More Information on Print/Save Options") [Supplementary Material ](https://www.biorxiv.org/content/10.64898/2026.10.15.759511v1.supplementary-material) [ Email](https://www.biorxiv.org/ "Email this Article") [ Share](https://www.biorxiv.org/) Discovery of a brain-penetrant CHI3L1 inhibitor as an oral modulator of neuroinflammation in Alzheimers disease Saurabh Upadhyay, Longfei Zhang, Baljit Kaur, Laura Calvo-Barreiro, Marianna Teplova, Moustafa Gabr bioRxiv 2026.10.15.759511; doi: https://doi.org/10.64898/2026.10.15.759511 This article is a preprint and has not been certified by peer review [[what does this mean?](https://www.biorxiv.org/about/FAQ#unrefereed)]. 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