TY - JOUR

T1 - The Effects of Salicyluric Acid, the Main Metabolite of Aspirin, on Lipid Peroxidation Induced by Iron and Copper Ions in a Lipid Membrane Model

AU - Timoshnikov, Viktor A.

AU - Koshman, Vladimir E.

AU - Deriskiba, Aleksandr A.

AU - Polyakov, Nikolay E.

AU - Kontoghiorghes, George J.

N1 - The Effects of Salicyluric Acid, the Main Metabolite of Aspirin, on Lipid Peroxidation Induced by Iron and Copper Ions in a Lipid Membrane Model / V. A. Timoshnikov, V. E. Koshman, A. A. Deriskiba [et al.] // International Journal of Molecular Sciences. – 2026. – Vol. 27, No. 3. – P. 1216. – DOI 10.3390/ijms27031216. – EDN XXEKCB. G.J.K. acknowledges the support from internal funds of the Postgraduate Research Institute of Science, Technology, Environment and Medicine, Cyprus. V.A.T., A.A.D., V.E.K. and N.E.P. (Institute of Chemical Kinetics and Combustion) acknowledge the core funding from the Russian Federal Ministry of Science and Higher Education (FWGF-2021-0003).

PY - 2026/1/26

Y1 - 2026/1/26

N2 - Salicyluric acid (SUA), the main metabolite of aspirin and a natural product, is known for its ability to chelate iron and other metal ions. In particular, the chelation and increased excretion of iron by SUA may contribute to the aspirin-induced iron deficiency anemia observed in long-term aspirin users. The redox activity of iron and copper complexes of drugs and also drug metabolites, such as SUA, is an important parameter of their overall toxicity profile, including the induction of ferroptosis, which has been associated with many diseases. In this context, the effect of SUA on iron- and copper-induced lipid peroxidation and also its localization within a model lipid membrane have been investigated. A combination of physicochemical methods, including Nuclear Magnetic Resonance (1H NMR), molecular dynamics (MD), and Nuclear Overhauser Effect Spectroscopy (1H NOESY), has been used to demonstrate that SUA does not promote the peroxidation of linoleic acid micelles in the presence of Fe(II) or Cu(II) ions. NMR experiments revealed that SUA incorporates into the lipid bilayer, which stabilizes the ligands and inhibits its metal chelation ability in comparison to the control. NOESY experiments and MD simulations further showed that SUA localizes shallowly within the membrane, interacting primarily with the head group and upper acyl chain regions of lipids. These findings provide crucial insights into the membrane redox reactivity and other behavior of SUA, explaining its lack of pro-oxidant activity and also highlighting its complex role in the pharmacological and toxicological effects on iron metabolism in long-term aspirin users.

AB - Salicyluric acid (SUA), the main metabolite of aspirin and a natural product, is known for its ability to chelate iron and other metal ions. In particular, the chelation and increased excretion of iron by SUA may contribute to the aspirin-induced iron deficiency anemia observed in long-term aspirin users. The redox activity of iron and copper complexes of drugs and also drug metabolites, such as SUA, is an important parameter of their overall toxicity profile, including the induction of ferroptosis, which has been associated with many diseases. In this context, the effect of SUA on iron- and copper-induced lipid peroxidation and also its localization within a model lipid membrane have been investigated. A combination of physicochemical methods, including Nuclear Magnetic Resonance (1H NMR), molecular dynamics (MD), and Nuclear Overhauser Effect Spectroscopy (1H NOESY), has been used to demonstrate that SUA does not promote the peroxidation of linoleic acid micelles in the presence of Fe(II) or Cu(II) ions. NMR experiments revealed that SUA incorporates into the lipid bilayer, which stabilizes the ligands and inhibits its metal chelation ability in comparison to the control. NOESY experiments and MD simulations further showed that SUA localizes shallowly within the membrane, interacting primarily with the head group and upper acyl chain regions of lipids. These findings provide crucial insights into the membrane redox reactivity and other behavior of SUA, explaining its lack of pro-oxidant activity and also highlighting its complex role in the pharmacological and toxicological effects on iron metabolism in long-term aspirin users.

KW - 1H NMR

KW - 1H NOESY

KW - aspirin

KW - chelator

KW - copper complex

KW - iron complex

KW - lipid peroxidation

KW - molecular dynamics

KW - salicyluric acid

KW - салицилуровая кислота

KW - хелатор

KW - перекисное окисление липидов

KW - комплекс железа

KW - комплекс меди

KW - молекулярная динамика

KW - 1H NOESY

KW - 1H ЯМР

KW - аспирин

UR - https://www.mendeley.com/catalogue/866232e5-e33c-3cf4-86e8-e63a102a0e1e/

UR - https://www.scopus.com/pages/publications/105030062816

UR - https://elibrary.ru/item.asp?id=89555027

U2 - 10.3390/ijms27031216

DO - 10.3390/ijms27031216

M3 - Article

C2 - 41683644

VL - 27

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

IS - 3

M1 - 1216

ER -