Lipid rafts are specialized microdomains within cellular membranes enriched with cholesterol and sphingolipids that play key roles in cellular organization, signaling, and homeostasis. This review highlights their involvement in protein clustering, energy metabolism, oxidative stress responses, inflammation, autophagy, and apoptosis. These findings clarify their influence on signaling, trafficking, and adhesion while interacting with the extracellular matrix, cytoskeleton, and ion channels, making them pivotal in the progression of various diseases. This review further addresses their contributions to immune responses, including autoimmune diseases, chronic inflammation, and cytokine storms. Additionally, their role as entry points for pathogens has been demonstrated, with raft-associated receptors being exploited by viruses and bacteria to increase infectivity and evade immune defenses. Disruptions in lipid raft dynamics are linked to oxidative stress and cellular signaling defects, which contribute to metabolic, neurodegenerative, and cardiovascular diseases. This review underscores their potential as therapeutic targets, discussing innovations such as engineered lipid raft transplantation. Advances in analytical techniques such as mass spectrometry have expanded our understanding of lipid raft composition and dynamics, opening new directions for research. By consolidating the current insights, we highlight the therapeutic potential of lipid rafts and highlight the need for further exploration of their molecular mechanisms.

Nitric oxide (NO) plays an important role in anoxic preconditioning to protect the heart against ischemia-reperfusion injuries. The present work was performed to study better the NO-cGMP-protein kinase G (PKG) signaling pathway in the activation of both sarcolemmal and mitochondrial ATP-sensitive K⁺ (K_ATP) channels during anoxic preconditioning (APC) and final influence on reducing anoxia-reperfusion (A/R)-induced cardiac damage in rat hearts. The upstream regulating elements controlling NO-cGMP-PKG signal-induced K_ATP channel opening that leads to cardioprotection were investigated. The involvement of both inducible and endothelial NO synthases (iNOS and eNOS) in the progression of this signaling pathway was followed. Final cellular outcomes of ischemia-induced injury after different preconditioning in the form of lactate dehydrogenase release, DNA strand breaks, and malondialdehyde formation as indexes of cell injury and lipid peroxidation, respectively, were investigated. The lactate dehydrogenase and malondialdehyde values decreased in the groups that underwent preconditioning periods with specific mitochondrial K_ATP channels opener diazoxide (100 μM), nonspecific mitochondrial K_ATP channels opener pinacidil (50 μM), S-nitroso- N-acetylpenicillamine (SNAP, 300 μM), or β-phenyl-1, N²-etheno-8-bromoguanosine-3′,5′-cyclicmonophosphorothioate, Sp-isomer (10 μM) before the A/R period. Preconditioning with SNAP significantly reduced the DNA damage. The effect was blocked by glibenclamide (50 μM), 5-hydroxydecanoate (100 μM), N^G-nitro-l-arginine methyl ester (200 μM), and β-phenyl-1, N²-etheno-8-bromoguanosine-3′,5′-cyclic monophosphorothioate, Rp-isomer (1 μM). The results suggest iNOS, rather than eNOS, as the major contributing NO synthase during APC treatment. Moreover, the PKG shows priority over NO as the upstream regulator of NO-cGMP-PKG signal-induced K_ATP channel opening that leads to cardioprotection during APC treatment.