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. This work was supported by the Key Research and Development Program of Shandong Province (Competitive innovation platform) (2026CXPT243), Jinan High-Level Innovation Teams from Universities and Research Institutes (202534016), the clinical-basic joint innovation team project of Shandong First Medical University (CX202408), The Science and Technology Development Fund, Macau SAR (File no. 0018/2024/RIA1, 0003/2025/NRP), and Shandong Province Health Science and Technology Innovation Team Construction Project (2024488). Faculty of Chinese Medicine and State Key Laboratory of Mechanism and Quality of Chinese Medicine, Macau University of Science and Technology, Macau, Macau SAR, China Shandong Provincial Key Laboratory of Biomechanics, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China Neck‐Shoulder and Lumbocrural Pain Hospital of Shandong First Medical University, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China Department of Molecular, Cell & Cancer Biology, UMass Chan Medical School, Worcester, MA, USA Innovation Technology Research Institute, Macau University of Science and Technology, Zhuhai, China Correspondence to Liang Shi, Lei Huang or Min Chen.
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To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. Shi, H., Shi, L., Huang, L. et al. Multi-scale integration identifies an ox-LDL-autophagy-inflammasome framework linking osteoporosis and neurodegeneration. npj Digit.
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