Bone is a dynamic tissue and is constantly being remodeled by bone cells. Metabolic reprogramming plays a critical role in the activation of these bone cells and skeletal metabolism, which fulfills the energy demand for bone remodeling. Among various metabolic pathways, the importance of lipid metabolism in bone cells has long been appreciated. More recent studies also establish the link between bone loss and lipid-altering conditions—such as atherosclerotic vascular disease, hyperlipidemia, and obesity—and uncover the detrimental effect of fat accumulation on skeletal homeostasis and increased risk of fracture. Targeting lipid metabolism with statin, a lipid-lowering drug, has been shown to improve bone density and quality in metabolic bone diseases. However, the molecular mechanisms of lipid-mediated regulation in osteoclasts are not completely understood. Thus, a better understanding of lipid metabolism in osteoclasts can be used to harness bone cell activity to treat pathological bone disorders. This review summarizes the recent developments of the contribution of lipid metabolism to the function and phenotype of osteoclasts.

The aged tumor microenvironment can impair antitumor T-cell function, but the molecular regulators that become limiting in this setting remain poorly defined. In a recent issue of Cell, Chen and colleagues harness in vivo CRISPR screening to compare the effects of genetic perturbations in tumor-reactive CD8+ T cells across young and aged hosts. The screen reveals that increased T-cell persistence or an effector-like transcriptional state does not necessarily translate into improved tumor control and identifies Dusp5 and Zfp219 as distinct functional regulators. DUSP5 broadly restrains ERK-dependent proliferation, and its loss improves tumor control in both young and aged mice. ZFP219, by contrast, preferentially limits cytotoxicity in aged hosts; its deletion increases granzyme expression and improves tumor control specifically in the aged setting. Human tumor datasets show that ZNF219 expression in intratumoral CD8+ T cells increases with age and is associated with poorer clinical outcomes. Moreover, Zfp219 loss enhances the response to PD-1 blockade in aged mice, producing complete tumor clearance in a subset of animals and durable protection after rechallenge. Together, these findings show that host age can reshape the functional consequences of T-cell perturbations and reveal age-dependent genetic vulnerabilities with potential therapeutic relevance.