Chronic low-grade inflammation is a hallmark of both metabolic and neurodegenerative diseases. In recent years, several studies have highlighted the pivotal role of systemic metabolic dysfunction, particularly insulin resistance, in shaping neuroinflammatory processes and contributing to impaired cognitive performance. Among metabolic disorders, type 2 diabetes mellitus has emerged as a major risk factor for the development of age-related neurodegenerative conditions, suggesting a complex and bidirectional crosstalk between peripheral metabolic imbalance and central nervous system function. This review aims to explore the cellular and molecular mechanisms underlying the interaction between metabolic dysregulation and brain inflammation. By integrating current findings from endocrinology, immunology, and neuroscience, this work provides a comprehensive overview of how chronic metabolic inflammation may contribute to the onset and progression of neurodegenerative conditions. This interdisciplinary approach could offer novel insights into potential therapeutic strategies targeting both metabolic and neuroinflammatory pathways.

Huntington’s disease (HD) is a detrimental neurodegenerative disease caused by the expansion of a CAG triplet in the HTT gene. This mutation leads to the production of mutant Huntingtin (Htt) protein with toxic gain-of-function. The mHtt is responsible in several ways for the establishment of an intricate pathogenetic scenario in affected cells, particularly in HD neurons. Among the features of HD, oxidative stress plays a relevant role in the progression of the disease at the cellular level. Mitochondrial dysfunction, bioenergetic deficits, Reactive Oxygen Species (ROS) production, neuroinflammation, and general reduction of antioxidant levels are all involved in the promotion of a toxic oxidative environment, eventually causing cell death. Nonetheless, neuronal cells exert antioxidant molecules to build up defense mechanisms. Key components of these defensive mechanisms are the nuclear factor erythroid 2-related factor 2 (NRF2) and peroxisome proliferator-activated receptor gamma coactivator-1 α (PGC-1α). Thus, this review aims to describe the involvement of oxidative stress in HD by exploring the roles of NRF2 and PGC-1α, crucial actors in this play. Finally, antioxidant therapeutic strategies targeting such markers are discussed.

Huntington’s disease (HD) is a detrimental neurodegenerative disease caused by the expansion of a CAG triplet in the HTT gene, ending in the production of abnormal Huntingtin (Htt) protein with toxic gain-of-function. The mutant protein (mHtt) is responsible in several ways for the establishment of an intricate pathogenetic scenario in affected cells, particularly in HD neurons. Among all the HD features, oxidative stress plays a relevant role in the progression of the disease at the cellular level. Mitochondrial dysfunction, bioenergetic deficits, Reactive Oxygen Species (ROS) production, neuroinflammation, and general reduction of antioxidants levels are all involved in the promotion of a toxic oxidative environment, eventually causing cell death. Nonetheless, neuronal cells exert antioxidant molecules to build up defense mechanisms. Key components of these defensive mechanisms are the nuclear factor erythroid 2-related factor 2 (NRF2) and peroxisome proliferator-activated receptor gamma coactivator-1 α (PGC-1α). Thus, aim of this re-view article is to describe the involvement of oxidative stress in HD by exploring the role of the NRF2 and PGC-1α, crucial actors in this play. Finally, antioxidant therapeutic strategies targeting such markers will be discussed.