Yiwen Fan

Background: Obesity-associated cognitive vulnerability involves peripheral metabolic organs, the circulation, and the neurovascular unit/blood–brain barrier (NVU/BBB). Whether adipose and hepatic dysfunction contribute through compartment-specific redox remodelling remains unclear. Methods: We searched PubMed/MEDLINE, Web of Science Core Collection, and Scopus for human, rodent, and cellular studies published from 1 January 2017 to 13 September 2026. Ninety-seven publications met the inclusion criteria. No meta-analysis or formal risk-of-bias assessment was undertaken. Results: Human studies associated adipose or hepatic dysfunction and circulating redox markers with brain and cognitive outcomes but rarely established tissue origin, temporal ordering, or mediation. Animal and cellular studies supported adipose mitochondrial and NOX-derived ROS, MASLD/MASH-related hepatic redox dysfunction, liver-derived signals, NVU/BBB impairment, and brain mitochondrial, inflammatory, synaptic, and cognitive changes. Conclusions: The adipose–liver–brain network is biologically plausible but remains unproven as a causal model. Future longitudinal and intervention studies should establish compartment specificity, temporal ordering, mediator reproducibility, reversibility, and domain-specific cognitive effects.

Drug resistance in acute promyelocytic leukemia (APL) remains clinically challenging despite the success of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) therapy. Existing explanations, including promyelocytic leukemia protein–retinoic acid receptor alpha (PML–RARα) mutations and alterations in individual death pathways, do not fully account for the heterogeneity of resistant phenotypes. This review proposes regulated cell death network (RCDN) remodeling as a testable framework for APL resistance. RCDN remodeling is defined as coordinated changes in network coupling, stress routing, and cellular death thresholds. We hypothesize that resistance emerges from coordinated adaptation across redox, survival signaling, and mitochondrial gating, rather than from defects in any single pathway. This predicts coupled shifts across multiple death modules and non-additive responses to combinatorial perturbations, distinguishing network-level remodeling from pathway-specific resistance. We further define experimental criteria for distinguishing network-level remodeling from pathway-specific resistance and discuss Tanshinone IIA (Tan IIA) as a preclinical multi-node perturbation probe.