2404 - Lipid Homeostasis Targeting via ABCA1 Preserves Normal Tissue Function and Enhances Tumor Response After Radiation

Purpose/Objective(s): Radiation-induced toxicity limits effective radiotherapy by causing lasting organ damage. This study investigates whether restoring ABCA1-mediated cholesterol transport can reduce radiation- or chemotherapy-related injury to normal tissues, such as salivary glands and kidneys, while maintaining tumor-killing effects.

Materials/Methods: C57BL/6 mice received partial total body irradiation (7.5 Gy) with hind-limb shielding (2.5% marrow sparing) to model clinically relevant radiation exposure. Rituximab was administered prior to irradiation, and salivary glands were analyzed 10 days post-treatment for structural injury, fibrosis, and lipid accumulation using histologic and lipid staining assays.

Complementary in vitro studies were performed using normal epithelial cell lines (HK-2, RWPE-1) and tumor cell lines (22RV1, LNCaP, and 786-O). Cells were treated with radiation (6 Gy) with or without cisplatin (40 µM administered 24 h before irradiation) in the presence or absence of lipid-modulating therapies, including rituximab (10 µg/mL, 24 h pre-irradiation), the LXR agonist GW3965 (5 µM), or methyl-ß-cyclodextrin (1 mM). Cellular proliferation and survival were quantified using real-time impedance-based growth assays. Primary endpoints included tissue injury, fibrosis, lipid accumulation, and differential effects on normal versus tumor cell survival.

Results: Partial TBI induced significant salivary gland injury characterized by acinar vacuolization, glandular atrophy, fibrosis, and increased lipid deposition compared with non-irradiated controls (all P<0.01). Rituximab treatment preserved glandular architecture and significantly reduced fibrosis and lipid accumulation (P<0.01).

In vitro, radiation and cisplatin significantly reduced proliferation of normal epithelial cells (P<0.01). Lipid-modulating therapies restored normal cell growth and attenuated treatment-induced injury (P<0.01). In contrast, tumor cell lines demonstrated enhanced radiosensitivity and chemosensitivity when combined with lipid-targeting interventions, resulting in greater growth inhibition and delayed proliferative recovery (P<0.01). Cholesterol-depleting strategies produced the strongest tumor-selective effects, simultaneously protecting normal cells while enhancing tumor cytotoxicity.

Conclusion: Radiation-induced disruption of lipid homeostasis represents a key mechanism underlying normal tissue injury. Pharmacologic restoration of ABCA1-dependent cholesterol efflux selectively protects normal tissues while maintaining or enhancing tumor response. Targeting lipid metabolism, therefore, represents a clinically translatable strategy to expand the therapeutic index of chemoradiotherapy and improve long-term survivorship outcomes.