Inspired by Zhang et al and Yang et al 2025.[1,2]

VCID – vascular cognitive impairment and dementia
IF – impact factor
VCIND – vascular cognitive impairment no dementia
JIA – juvenile idiopathic arthritis
RAS – family of genes that encode small GTPase proteins (literally short for RAt Sarcoma after its discovery in the 1980’s during rat sarcoma virus studies)
GTPase – enzyme that binds GTP (essentially an intracellular molecular switch, which is on when binding GTP and off when binding GDP)
GTP – guanosine triphosphate
GDP – guanosine diphosphate
PL – phospholipid (usually glycerophospholipids ie a PL with a glycerol backbone)
PUFA – polyunsaturated fatty acid
PL-PUFA – PL containing PUFA (the major component of cell membranes)
ROS – reactive oxygen species
GPX4 – glutathione peroxidase 4 (a lipid antioxidant enzyme that converts lipid-OOH to lipid-OH)

– key to acronyms

I have seen the term ferroptosis coming up quite regularly in my acupuncture searches recently, so I thought I should take a closer look at what exactly it means. To that end, there have been a couple of relevant papers recently in Frontiers in Aging Neuroscience (IF 4.1).[1,2] Both are from Tianjin, which is on the east coast of China, just southeast of Beijing.

The first of those led me to a review paper in the journal Cell (IF 45.5),[3] which in turn led to the paper that first described ferroptosis in 2012.[4] I should not feel too bad about not knowing what the term means, since it was first coined 40 years after I entered medical school! Apologies for reminding you of my career history and perhaps therefore my propensity for the onset of VCID. Or perhaps we should start with VCIND, which I highlighted on this blog in 2019. That is a blog worth re-reading before going further here.

We have all heard of apoptosis, which was first described in 1972.[5] The term combines ‘apo’ from the Greek meaning ‘away from’ with ‘ptosis’ meaning falling, as in the dropping of leaves from a tree. This etymology metaphorically describes the natural process of parts (cells) falling away or dying as a function of an organism’s normal processes.

We have met pyroptosis on this blog a few times from 2022 to a more recent post on JIA. The Greek ‘pyro’ means fire or fever, and this form of cell death is the most pro-inflammatory. It was first described in 2001.[6]

Necroptosis is a form of regulated necrosis that combines features of both apoptosis and necrosis. It was first described in 2005.[7]

Finally, ferroptosis was described by researchers from Columbia University in New York who were investigating oncogenic RAS mutant cell lines and how they could be killed by erastin – an inhibitor of the cystine/glutamate antiporter system X_c^–.[4] I’ll come back to that!

Ferroptosis is a form of regulated non-apoptotic cell death driven by iron-dependant lipid peroxidation particularly in PL-PUFAs. That is a bit of a mouthful isn’t it! In basic terms cells die as a result of too much ‘rusting’ of their cell membranes. I am using the term ‘rusting’ incorrectly here, but it gives a certain mental image of deterioration that is close to the truth. Bound Fe³⁺ is transported into cells and converted to Fe²⁺. This is bound by cytosolic ferritin, but any excess intracellular and Fe²⁺ catalyses peroxidation (formation of -OO-) of certain carbon carbon double bonds in PL-PUFAs.

Ironically, intracellular organelles called peroxisomes, which have a function of dealing with ROS (peroxide and related free radicals), create certain PLs called plasmalogens that are particularly vulnerable to this process of peroxidation. In the absence of excess unbound cytosolic Fe²⁺, plasmalogens have a role of mopping up ROS and therefore protecting the PL bilayer of membranes, but in the presence of Fe²⁺, they actually make the situation worse by creating peroxide groups without the need for ROS.

Back to the cystine/glutamate antiporter system X_c^–, which transports cystine into the cell in exchange for glutamate (hence antiporter as opposed to uni- or syn-). Cystine is a dimer of cysteine, where the two amino acids are connected by a covalent bond between their sulphur atoms. Intracellular cystine is used to form glutathione, which is a combination of cysteine and (again) glutamate (don’t worry, there is lots of it inside the cell) with glycine (the smallest of the amino acids) tagged on at the end.

GPX4 is a lipid specific antioxidant selenoprotein enzyme that uses glutathione as a cofactor in converting lipid hydroperoxide (lipid-OOH) to non-toxic lipid alcohols (lipid-OH). It requires 2 glutathione molecules each time.

Selenoproteins are rare but essential. There are about 25 of them in humans (<0.1% of all proteins). Selenium sits in the place of sulphur in cysteine to create selenocysteine, which makes the later more reactive.

So, that is all a bit complex molecular stuff, what about acupuncture and VCID. Well, the story is not entirely satisfactory because so far all we have are pieces of the complex puzzle. Acupuncture seems to influence a number of the factors involved in the process of ferroptosis. For example, it increases GPX4 and effectively reduces the quantity of unbound cytosolic Fe²⁺ by altering factors that bind and transport it.

Ferroptosis appears to be a key factor in the progression neurodegenerative diseases, and it could be that acupuncture helps to mitigate this process. When we reach a certain age, perhaps we should all be getting it prophylactically.

References

1          Zhang W, Li R, Lu D, et al. Phospholipids and peroxisomes in ferroptosis: the therapeutic target of acupuncture regulating vascular cognitive impairment and dementia. Front Aging Neurosci. 2025;17:1512980. doi: 10.3389/fnagi.2025.1512980

2          Yang X, Li B, Wu L, et al. Acupuncture treatment of vascular cognitive impairment through peripheral nerve stimulation pathway: a scoping review. Front Aging Neurosci. 2025;17:1515327. doi: 10.3389/fnagi.2025.1515327

3          Stockwell BR. Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. Cell. 2022;185:2401–21. doi: 10.1016/j.cell.2022.06.003

4          Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72. doi: 10.1016/j.cell.2012.03.042

5          Kerr JFR, Wyllie AH, Currie AR. Apoptosis: A Basic Biological Phenomenon with Wideranging Implications in Tissue Kinetics. Br J Cancer. 1972;26:239–57. doi: 10.1038/bjc.1972.33

6          Cookson BT, Brennan MA. Pro-inflammatory programmed cell death. Trends Microbiol. 2001;9:113–4. doi: 10.1016/s0966-842x(00)01936-3

7          Degterev A, Huang Z, Boyce M, et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol. 2005;1:112–9. doi: 10.1038/nchembio711

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Declaration of interests MC

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