# Project 3: Metabolic stress induces mitochondrial dysfunction through STARD1 and SAB leading to HCC

> **NIH NIH P01** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2024 · $532,804

## Abstract

PROJECT SUMMARY – PROJECT 3
The incidence of NASH-driven HCC is expected to increase worldwide due to its association with the obesity
and type-2 diabetes epidemic. Chronic ER stress and overnutrition synergize to drive NASH-HCC and metabolic
stress affects ER and mitochondrial function through mitochondria-associated membranes (MAM). SAB
(SH3BP5) and STARD1, two mitochondrial-resident proteins induced by ER stress, contribute to ER-
mitochondria crosstalk in acute liver injury. STARD1 transfers cholesterol to the mitochondrial inner membrane
for metabolism to bile acids (BAs) in the alternative (acidic) pathway. SAB acts as a docking protein required for
sustained p-JNK activation through mitochondrial dysfunction and an amplification of reactive oxygen species
generation. Although basal levels of STARD1 and SAB are low, their expression increases in human NASH-
HCC samples. We hypothesize that SAB and STARD1 act as complementary partners and downstream
mediators of the NRF2/ATF6/FBP-1 loss network to induce mitochondrial dysfunction and metabolic
reprogramming through the switch of BAs synthesis from the classic to the alternative pathway. Specific aims:
Aim 1. How does STARD1-SAB/JNK promote NASH-driven HCC? We hypothesize that STARD1-SAB/JNK
alters BA homeostasis leading to HCC development. 1.1. How does BAs generated through the alternative
pathway lead to loss of FBP-1? 1.2 What is the effect of STARD1-SAB-JNK ablation on BAs and FBP-1 expression
in human HCC PDXs/spheroids? 1.3 Determination of the tumorigenic potential of HCC cell lines from MUP-
uPA/NRFAct-Hep mice. Aim 2. How does STARD1-SAB/JNK axis alter the lipid composition of
MAMs/Mitochondria and cause ER stress to promote NASH-driven HCC? We hypothesize that STARD1
regulates mitochondrial cholesterol content and SAB/JNK changes MAM lipid composition via MFN-2
degradation, leading to metabolic reprogramming for HCC. 2.1 Determination of the lipidome of
MAMs/Mitochondria from MUP-uPA/NRF2Act-Hep-derived HCC and the role of STARD1-SAB/JNK knockdown.
2.2 Analyze MAM/mitochondrial lipid composition in human HCC PDXs/spheroids. 2.3 How does ER stress
induce STARD1-SAB expression to promote HCC? Aim 3. How does STARD1-SAB/JNK metabolic
reprogramming lead to NASH-driven HCC? We postulate that STARD1-induced cholesterol trafficking and
SAB-mediated JNK activation suppress oxidative phosphorylation, increase glycolysis and impair mitophagy to
favor HCC development. 3.1 Determination of mitochondrial function, glycolysis and mitophagy in MUP-
uPA/NRFAct-ΔHep mice. 3.2 Examination of mitochondrial function and glycolysis of HCC cell lines and human
PDXs/spheroids. 3.3 Impact of STARD1-SAB/JNK in stabilization of HIF-1. Thus, it is anticipated that the
integration of our work with Projects 1 and 2 and Cores 1 and 2 will advance our understanding of HCC
pathogenesis and lead to new therapeutic approaches.

## Key facts

- **NIH application ID:** 10935867
- **Project number:** 1P01CA281819-01A1
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** NEIL KAPLOWITZ
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $532,804
- **Award type:** 1
- **Project period:** 2024-09-09 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10935867

## Citation

> US National Institutes of Health, RePORTER application 10935867, Project 3: Metabolic stress induces mitochondrial dysfunction through STARD1 and SAB leading to HCC (1P01CA281819-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10935867. Licensed CC0.

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