Multi-scale integration identifies an ox-LDL-autophagy-inflammasome framework linking osteoporosis and neurodegeneration

Osteoporosis (OP) and neurodegeneration frequently co-occur with advancing age, but the biological processes linking skeletal and neurological decline remain incompletely understood. To investigate the metabolic-inflammatory axis connecting skeletal and neurological degeneration, we integrated cross-tissue multi-omics, single-cell transcriptomics, in vitro macrophage assays, and systems-level ordinary differential equation (ODE)-based modeling. Population-level and genetically informed analyses consistently implicated metabolic burden and lipid-associated stress in both disease domains, whereas physical activity showed protective associations. Cross-tissue and single-cell analyses identified convergent autophagy- and inflammasome-related programs, while cross-tissue multi-omics highlighted a PHF23-MCL1-CLN3 autophagy-associated molecular module. In RAW264.7 macrophages, oxidized low-density lipoprotein (ox-LDL) exposure induced inflammatory activation, pro-inflammatory polarization, and autophagy-associated dysregulation, while PHF23 perturbation modified ox-LDL-induced inflammatory responses. A 12-state ODE model further provided a hypothesis-generating representation of dynamic interactions among ox-LDL-associated metabolic stress, autophagy regulation, inflammasome activation, macrophage polarization, and tissue-damage-related states. Together, these multi-scale findings provide convergent support for an ox-LDL-autophagy-inflammasome-associated framework linking metabolic dysfunction with skeletal and neurological degeneration and generate testable hypotheses for further experimental investigation.