Cancer-associated cachexia (CAC) is a multifactorial metabolic syndrome characterized by systemic inflammation and progressive loss of adipose and muscle mass that cannot be reversed by nutritional support. White adipose tissue (WAT) is among the earliest and most severely affected tissues, and preserving WAT has been shown to protect muscle and improve outcomes in murine CAC models. Yet, the mechanisms driving WAT loss remain poorly understood. Emerging evidence suggests that excessive mitophagy disrupts adipocyte mitochondrial homeostasis, promoting lipolysis, inflammation, and metabolic deterioration. We propose that fat cells sense tumor-derived hypoxic/pseudohypoxic cues that induce BNIP3, a key mitophagy receptor, leading to aberrant BNIP3-mediated mitophagy, mitochondrial fragmentation, and metabolic dysfunction. To test our hypothesis, we leveraged engineered adipose tissue models, including a 3D platform that enables direct encapsulation of mature adipocytes without the need for in-vitro differentiation, preserving their native metabolic phenotype. Using this system, along with ASC cultures and thermogenic and white adipocytes, we evaluated the impact of B16F10 melanoma conditioned media (CM), known to induce cachexia, on BNIP3 expression, mitochondrial dynamics, and lipid metabolism. Across models, B16F10-secreted factors induced a 3-fold increase in BNIP3, accompanied by mitochondrial fragmentation, upregulation of fission markers, and enhanced fatty acid oxidation in white adipocytes. To functionally test the role of BNIP3, we used our lab-developed lipid-coated mesoporous silica nanoparticles (LCMSNs) that efficiently load siRNA and exhibit prolonged retention in fat depots, as demonstrated in our biodistribution studies. BNIP3-siRNA LCMSNs reduced BNIP3 overexpression in our 3D mature adipocyte constructs exposed to melanoma CM. Silencing BNIP3 overexpression resulted in decreased fatty acid oxidation and a trend toward reduced fission-related gene expression. Together, these findings identify BNIP3-mediated mitophagy as a driver of adipocyte dysfunction in CAC and showcase two innovative tools, a physiologically relevant 3D mature adipocyte model and a fat-retained gene-delivery nanoparticle, to dissect and therapeutically target adipose tissue wasting. Our work positions BNIP3 silencing via LCMSNs as a promising strategy to preserve WAT and mitigate metabolic decline during cancer cachexia. Funding sources: The Max and Minnie Tomerlin Voelcker Fund 2025 This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Ortiz et al. (2026) studied this question.