Free fatty acids (FFAs) play numerous vital roles in the organism, such as contribution to energy generation and reserve, serving as an essential component of the cell membrane, or as ligands for nuclear receptors. However, the disturbance in fatty acid homeostasis, such as inefficient metabolism or intensified release from the site of storage, may result in increased serum FFA levels and eventually result in ectopic fat deposition, which is unfavorable for the organism. The cells are adjusted for the accumulation of FFA to a limited extent and so prolonged exposure to elevated FFA levels results in deleterious effects referred to as lipotoxicity. Lipotoxicity contributes to the development of diseases such as insulin resistance, diabetes, cardiovascular diseases, metabolic syndrome, and inflammation. The nonobvious organs recognized as the main lipotoxic goal of action are the pancreas, liver, skeletal muscles, cardiac muscle, and kidneys. However, lipotoxic effects to a significant extent are not organ-specific but affect fundamental cellular processes occurring in most cells. Therefore, the wider perception of cellular lipotoxic mechanisms and their interrelation may be beneficial for a better understanding of various diseases’ pathogenesis and seeking new pharmacological treatment approaches.

Despite decades of advancements in HIV treatment, the persistence of viral reservoirs necessitates lifelong therapy, complicating efforts to fully control the infection. Nucleoside reverse transcriptase inhibitors (NRTIs) remain a cornerstone of HIV treatment, but long-term use is associated with side effects, including lipid metabolism disruption and neurocognitive disorders. There is a gap in understanding the safety of antiretrovirals and their impact on lipid toxicity in the central nervous system. To address this issue, our study investigated the impact of NRTIs, specifically lamivudine and zidovudine, on lipid metabolism and insulin resistance in the SH-SY5Y dopaminergic neuronal cell line. We also compared these effects to those induced by two free fatty acids, palmitic and docosahexaenoic acids. We measured mitochondrial superoxide levels, fatty acid binding proteins 4 and 5, and overall lipid content. Additionally, we assessed insulin resistance by analyzing the phosphorylation of mitogen-activated protein kinases and phosphoinositide 3-kinase, as well as the concentrations of insulin receptor substrate 1 and insulin receptor. The results demonstrated that NRTIs led to reduced fatty acid binding protein 4 levels and lipid content, similar to the effects observed with fatty acids. Moreover, lamivudine and zidovudine increased mitochondrial superoxide levels. Lamivudine also amplified the phosphorylation level of ERK. These findings suggest that NRTIs may contribute to lipotoxicity in dopaminergic neurons, warranting further investigation into their long-term effects on the central nervous system.

Formerly recognized as an opioid receptor, the sigma-1 receptor (σ1R) is a multifunctional chaperone protein that plays a crucial role in regulating neuronal signaling, neuroprotection, and synaptic plasticity. Increasing evidence highlights a tight functional association between the σ1R and the N-methyl-D-aspartate receptor (NMDAR), a central mediator of excitatory neurotransmission and calcium-dependent neuronal processes. This review summarizes the shared signaling pathways underlying σ1R and NMDAR activity, including calcium homeostasis, calcium/calmodulin-dependent protein kinases (CaMKs), protein kinase C (PKC), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), and mitogen-activated protein kinase (MAPK) cascades, as well as transcriptional regulators such as cAMP response element-binding protein (CREB), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and B-cell lymphoma 2 (Bcl-2). Experimental data demonstrate that pharmacological agents initially characterized as NMDAR antagonists—such as ketamine, dextromethorphan, and memantine—also interact with σ1R, suggesting that their therapeutic efficacy may arise from coordinated modulation of both receptor systems. These findings collectively indicate that the σ1R is a key regulatory element enabling proper NMDAR function and that disruption of this interaction may contribute to excitatory imbalance implicated in the pathophysiology of neuropsychiatric disorders. Recognizing the σ1R–NMDAR crosstalk as an integrated signaling axis may thus inform the development of dual-target therapeutic strategies aimed at improving neuronal resilience and clinical outcomes in psychiatric and neurodegenerative diseases.