237 Background: Androgen deprivation therapy (ADT) is central to prostate cancer care but accelerates cardiometabolic toxicity, particularly among men with obesity. The biological basis of this differential vulnerability is unknown. We hypothesized that obesity modifies chromatin accessibility responses to ADT, reflecting distinct transcriptional programs linked to inflammation and metabolism. Methods: Matched peripheral blood mononuclear cell samples (pre- and on-ADT) from 11 men with prostate cancer were analyzed by bulk ATAC-seq. Reads were aligned to GRCh38 with Tn5 correction and ENCODE blacklist removal. Peaks were called using MACS2 and unified via DiffBind. Differential accessibility was normalized by library size ( FDR < 0.05). Pathway enrichment used MSigDB Hallmark sets and GSEA. Participants were stratified by BMI < 25 kg/m² (lean) or ≥ 30 kg/m² (obese). While pre vs on-ADT changes were assessed across all pairs, BMI-stratified differences showed the most distinct patterns and are presented in the results. Results: Median age was 69 years; 50% White, 42% Black; BMI 30.0 ± 7.6 kg/m² (range 21.8–51.4); 66 % had hypertension, 50 % diabetes, and 42 % baseline cardiovascular disease. Most (83 %) received combined ADT + XRT. ADT induced widespread chromatin remodeling without locus-level significance after FDR correction but demonstrated divergent pathway activation by BMI. Obese men showed up-regulation of immune-metabolic programs (TNF-α/NF-κB, IL2–STAT5, Complement, mTORC1), whereas lean men showed repression of these same modules (Table). Conclusions: This first-in-human bulk ATAC-seq study reveals BMI-dependent epigenetic remodeling during ADT. Obese men exhibit activation of immune-metabolic pathways consistent with a pro-inflammatory, cardiometabolic phenotype, while lean men show reciprocal suppression. Integrating adiposity metrics with epigenomic profiling may refine cardio-oncologic risk stratification and guide precision mitigation strategies for men receiving ADT. Differential pathway enrichment during ADT by BMI group. Pathway (Obese ≥ 30) NES / Adj p Pathway (Lean < 25) NES / Adj p TNF-α via NF-κB 1.96 / 1.8×10⁻⁶ TNF-α via NF-κB –2.20 / 1.1×10⁻⁸ IL2–STAT5 signaling 1.63 / 6.8×10⁻⁴ IL2–STAT5 signaling –1.84 / 9.1×10⁻⁵ Complement 1.54 / 1.4×10⁻³ UV Response –1.70 / 0.004 Inflammatory response 1.67 / 6.8×10⁻⁴ Inflammatory response –1.65 / 0.005 KRAS Signaling 1.4 / 0.0203 KRAS signaling –1.51 / 0.035 Allograft Rejection 2.01 / 8.09 × 10⁻⁷ Allograft rejection –1.59 / 0.006 Apoptosis 1.68 / 6.84 × 10⁻⁴ Interferon-γ Response 1.44 / 0.018 mTORC1 signaling 1.33 / 0.032 Hypoxia 1.39 / 0.02 NES = normalized enrichment score; positive = activation; Negative = suppression after ADT vs pre-ADT.
Kunhiraman et al. (Sun,) studied this question.