# Novel role of RIPK3-dependent necroptosis pathway in lung and kidney fibrosis

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $523,411

## Abstract

Abstract
Fibrosis is a pathogenic process in organs (e.g., lung, kidney) involving the excess deposition of extracellular
matrix (ECM) leading to loss of organ homeostasis. Fibrosis is the hallmark of progressive chronic kidney
diseases as a common pathogenic response to injury. Similarly, end-stage lung diseases are often
characterized by lung fibrosis. Recent studies suggest that necroptosis, a genetically-programmed form of cell
death that is regulated by receptor-interacting protein-1 and -3 (RIPK1, RIPK3) kinases, may have emerging
significance in human disease. Little is currently known of the role of RIPK3 in the pathogenesis of organ
fibrosis. We have exciting preliminary data that RIPK3 can exert crucial functions in experimental models
of kidney and lung fibrosis. Intriguingly, mice deficient in RIPK3, but not in its signaling target the mixed
lineage kinase domain-like protein (MLKL), were protected against kidney fibrosis. We have also identified
a RIPK3-mediated signaling pathway that regulates fatty acid (FA) metabolism by activating ATP citrate
lyase (ACL), and contributes to kidney fibrosis. In contrast, mice deficient in either RIPK3 or MLKL were
susceptible to pulmonary fibrosis. These studies suggest that RIPK3 may represent a novel mediator of
organ fibrosis with differential organ or tissue-specific effects.
The endogenous gaseous molecule carbon monoxide (CO) has been implicated as an experimental
therapeutic modality in organ injury. Our published studies indicate that physiologic low-dose CO can mitigate
fibrosis in unilateral ureteral obstruction (UUO)-induced kidney fibrosis, and in bleomycin (BLM)-induced
pulmonary fibrosis. Therefore, we hypothesize that RIPK3 represents an important mediator of organ fibrosis
through MLKL-independent and MLKL–dependent pathways. A RIPK3-dependent (MLKL-independent)
signaling pathway and downstream regulation of the FA synthesis pathway contributes to the development of
kidney fibrosis. In contrast, a RIPK3 and MLKL dependent pathway can inhibit pulmonary fibrosis. Moreover,
we hypothesize that CO confers protection against multi-organ fibrosis by targeting either RIPK3 and/or FA-
dependent pathways. RIPK3 and/or FA-biosynthetic proteins potentially serve as diagnostic biomarkers in
predicting the severity of organ fibrosis and the efficacy of CO therapy. We will test these hypotheses in the
following Specific Aims: Specific Aim 1: To characterize the function of RIPK3 and MLKL in the pathogenesis
of organ fibrosis; Specific Aim 2: To determine the pathogenic contribution of RIPK3-regulated fatty acid (FA)
synthesis in fibrotic organs; Specific Aim 3: To determine the role of the RIPK3 and the FA synthesis pathways
in the therapeutic effects of CO in experimental lung and kidney fibrosis, and in human fibrosis.

## Key facts

- **NIH application ID:** 9981806
- **Project number:** 5R01HL133801-04
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** MARY E CHOI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $523,411
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9981806

## Citation

> US National Institutes of Health, RePORTER application 9981806, Novel role of RIPK3-dependent necroptosis pathway in lung and kidney fibrosis (5R01HL133801-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9981806. Licensed CC0.

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