Fig. 2

Schematic diagram illustrating two pathways associated with the production of HNE: the enzymatic pathway and the non-enzymatic pathway. In the enzymatic pathway, the PLA2 cleaves n-3 PUFAs and produces EPA and DHA. The cleavage product of the n-6 PUFA family is arachidonic acid (AA). EPA and DHA inhibit NF-kB, NLRP3, GPCR, and TGF-β signalling. AA, produced by PLA2 and catalysed by COX-1, COX-2, and 5-LOX, results in PGH2 and LTB4, leading to the production of proinflammatory mediators. AA is also converted into HNE via 15-LOX. For the non-enzymatic pathway, the free radical lipid peroxidation primarily produces HNE. Abstraction of the allylic hydrogen atom remains lipid radical, resulting in a carbon-centred alkyl radical; eventually, the carbon-centred alkyl radical produces lipid peroxyl radical. The lipid peroxyl radical may generate HNE via five mechanisms. (1) The hydroperoxyl radical is produced as a result of the hydrogen abstraction of the lipid peroxyl radical. The alkoxyl radical produces HNE via β-scission, cyclisation, and the presence of the transition metal ion Fe²⁺. (2) Hydroperoxyl dioxetane, formed through cyclisation, produces peroxyl dioxetane through oxygenation. Peroxyl dioxetane then produces 4-HPNE by fragmentation. Here 4-HPNE becomes HNE by hydrogen abstraction. (3) The hydroperoxyl radical is produced by hydroperoxyl dioxetane through cyclisation. HNE is produced from hydroperoxyl dioxetane as a result of fragmentation and the abstraction of hydrogen. (4) The reaction between Fe²⁺ and bicyclic endoperoxides creates alkoxyl radicals. These alkoxyl radicals cause HNE through oxygenation and fragmentation processes. (5) 15-HPETE and 13-HPODE, produced by the alkoxyl radicals through Hock rearrangement and cleavage, are known as immediate precursors of HNE