June 7, 2023

NAC Improves Lupus Symptoms

Exploring the role of ferroptosis in lupus, and its implications for other diseases
N-acetylcysteine (NAC) improves symptoms of systemic lupus erythematosus (SLE) and suggests that controlling ferroptosis may be a key element of this disease.


Abbasifard M, Khorramdelazad H, Rostamian A, et al. Effects of N-acetylcysteine on systemic lupus erythematosus disease activity and its associated complications: a randomized double-blind clinical trial study. Trials. 2023;24(1):129. 

Study Objective

To assess the effects of N-acetylcysteine (NAC) on systemic lupus erythematosus (SLE) disease activity and outcome

Key Take-Away

N-acetylcysteine (NAC) improves symptoms of systemic lupus erythematosus (SLE) and suggests that controlling ferroptosis may be a key element of this disease.


Randomized, double-blind, controlled clinical trial study


Eighty patients with SLE were recruited and divided into 2 groups: 40 patients received NAC treatment and 40 patients served as a control group receiving only standard therapies. 

There were no significant differences between the characteristics of the 2 groups.


Those in the experimental group received a total of 1,800 mg/day of NAC divided into three 600 mg doses, taken at 8-hour intervals. The control group received standard of care.

Study Parameters Assessed

All patients were routinely examined and periodically tested at baseline. These tests included:

  • Blood cell count
  • Kidney and renal function
  • Urine analysis
  • Laboratory tests relevant to SLE: anti-dsDNA, anti-nuclear antibody (ANA) titer, serum complement C3 and C4 concentrations, total hemolytic activity (CH50), and proteinuria

The activity of lupus disease before and after treatment was measured according to the British Isles Lupus Assessment Group (BILAG) scoring system and the SLE Disease Activity Index (SLEDAI) score.

Primary Outcome

To assess the effect of NAC supplementation on objective and subjective measures of SLE

Key Findings

After taking NAC for 3 months, the experimental group experienced statistically significant decreases in both BILAG score (P= 0.023) and SLEDAI scores (P=0.034) compared with their baseline. In intergroup comparison, the NAC group’s BILAG score was significantly lower than the control group’s at 3 months (P=0.021). The SLEDAI score of the NAC group was also significantly lower than the control groups after 3 months (P=0.030). No significant changes were observed in BILAG score of the control group at the 3-month timepoint compared to their baseline level (P>0.05). 

The BILAG scores that quantify disease activity by organ system showed significant decreases in the NAC group compared to their baseline levels: measuring improvements in general (P=0.018), mucocutaneous (P=0.003), neurological (P=0.015), musculoskeletal (P= 0.048), cardiorespiratory (P=0.047), renal (P=0.025), and vascular (P=0.048) complications, from the disease.

CH50 increased significantly in the NAC group from 81 to 95% (P=0.04), a finding consistent with disease improvements. 

No adverse events were reported in the study subjects.


This article was supported by a grant from the Deputy of Research, Rafsanjan University of Medical Sciences. The authors report no competing interests.

Practice Implications & Limitations

There are 2 ways for us to view these results. The simplest interpretation is that NAC successfully reduces symptoms of SLE without producing adverse effects and should now be added to our protocols for treating this disease.

A second and wider interpretation is that this study confirms a new theory explaining the etiology of SLE and other autoimmune disorders. If this new theory is accepted, this understanding may be translated into a broader treatment protocol for SLE specifically and perhaps to other autoimmune conditions. 

Let’s start with simple first. SLE is a disease with high oxidative stress. NAC acts as a precursor to glutathione and can reduce the highly oxidative environment of this disease.  NAC was reported useful in 2001 by Suwannaroj et al in a mouse model of SLE. These researchers had tested both NAC and cysteamine (CYST) on autoimmune disease, glomerulonephritis, and mortality in the female B/W mouse model and reported both reduced symptoms and improved mortality, concluding that “sntioxidants may be a beneficial adjunctive therapy in the treatment of human SLE.”1

In 2002, Gergely  et al reported that when comparing a group of 25 SLE patients, 10 rheumatoid arthritis (RA) patients, and 25 healthy controls, those with SLE had diminished intracellular glutathione.2 This association between low glutathione and SLE initiated trials using NAC at different doses. 

In 2012, Lai et al reported the results of a randomized blinded clinical trial using various doses of NAC on 36 SLE patients for 3 months. Groups received either placebo or 1.2 g, 2.4 g, or 4.8 g of NAC per day. The control group included 42 healthy individuals. The same BILAG and SLEDAI indexes were used to score disease symptoms as in our current study. NAC doses up to 2.4 g/day were well tolerated, but at 4.8 g/day, about a third of the patients reported nausea. Neither the placebo group nor the group taking 1.2 g/day showed significant improvement in symptoms. Those taking higher doses (2.4 and 4.8 g/day) did have significant improvements with significant score changes at 1 month and continuing throughout the 3 months of the study.3

The current study will help determine a minimal effective dose. The simple take-home from this study is that “the addition of 1,800 mg NAC to the treatment regimen of patients with lupus can improve the outcomes of the disease and decrease the activity and complications of lupus disease.”

The deeper and, one hopes, longer-lasting message from these results is that they support a new theory that some autoimmune diseases, in particular SLE, are the result of ferroptosis and should be treated in this light.

In June 2022, Benjamin Lai et al hypothesized that autoimmune diseases in general were triggered by an excess of dying cells. These researchers argued that among the potential “factors that trigger autoimmunity is the abnormal induction of cell death and the inadequate clearance of dead cells that leads to the exposure or release of intracellular contents that activate the immune system” and that a form of programmed cell death called ferroptosis may be the lead suspect in this process.4

Just a few months earlier, Chen et al had argued essentially the same thing, suggesting that in SLE, ferroptosis played the key role.5

Let’s back up and discuss ferroptosis in greater detail.

Ferroptosis is a form of programmed cell death that is nonapoptotic. The term ‘apoptosis’ was coined in 1972 to describe the specific form of cell death in which cells commit suicide in an orderly, sequential manner by fissuring into membrane-bound apoptotic bodies. This process was the one and only form of programed cell death scientists were aware of. However, apoptosis is now considered just one of several different types of programmed cell death that may occur in cells. 

The original term ‘apoptosis’ was derived from 2 Greek words: the prefix “apo-”, translated as “separation”, and the suffix, “-ptosis”, translated as “falling off.”

The combined term apoptosis metaphorically references the falling off of leaves from trees in autumn. Scientists now talk of other nonapoptotic forms of programmed death such as pyroptosis, necroptosis, and ferroptosis. These new names retain the -ptosis suffix and are still forms of programmed cell death, just not the originally identified process of apoptosis. In ferroptosis, the prefix “ferro-“ derives from ferrum, as in iron. It is the chemical reactivity of iron that drives this mechanism of cell death.

Ferroptosis, in contrast to the relatively “clean” apoptosis, is messy. It leads to “a sort of explosive necrotic death able to induce inflammatory response.”6 The cells still die in response to dedicated molecular machinery, programmed into cellular DNA, and can be induced or prevented through various pharmacological or genetic manipulations. 

The messy aspect of ferroptosis shouldn’t be skimmed over. The process triggers inflammation and leaves a clutter of cell fragments in circulation. While apoptosis is a neat and tidy way to recycle cell materials; ferroptosis is far less so, leading to an accumulation of cell waste materials in the bloodstream, which may initiate and promote autoimmune disease. 

Our knowledge of ferroptosis is recent. The term was only first used in 2012, even if aspects of this form of cell death were reported years before. Harry Eagle described what now would be called ferroptosis in the 1950s when he reported the manner in which cysteine-deficient cells die.7 Without cysteine, he could not grow cells in culture, and they perished in a distinctive manner. 

In 1977, Shiro Bannai linked this death by cysteine starvation to glutathione depletion and reactive oxygen species accumulation.8

Ferroptosis is now defined as an iron-dependent form of regulated cell death that occurs through accumulation of lipid-based reactive oxygen species (ROS) when glutathione (GSH)-dependent lipid peroxide repair systems have been compromised.9 The mechanisms that drive this suicidal process are distinct and different from apoptosis, necrosis, autophagy, and other forms of cell death. We know that this process is driven by iron’s peroxidation of lipids to produce lethal lipid species that fatally damage the integrity of cell membranes. Distinctively, both iron chelators and vitamin E may halt the process.10,11

In simple terms, iron serves as both a catalyst and reactive force to oxidize the polyunsaturated fatty acids (PUFA) that make up cell membranes. Glutathione and other antioxidants that would normally halt these oxidative reactions are prevented from doing so. Cell membranes degrade, and various autophagy processes are set into motion so that the cell dies. 

Remember these 3 hallmarks of ferroptosis:

  1. The free iron that drives Fenton reactions to produce ROS
  2. The oxidation of phospholipids containing polyunsaturated fatty acid (PUFA)–damaging cell membranes
  3. A failure to repair the damage

These oxidation reactions are normally controlled by glutathione (GSH), which would normally prevent ferroptosis from proceeding but in the case of SLE fails to do so.12

There are 2 general and widely different clinical arenas in which to consider the role of ferroptosis. Ferroptosis plays a role in the development of various vascular and neurodegenerative diseases.13 It also plays a role in controlling cancer. Now a third arena could be added: Ferroptosis plays a crucial role in autoimmune diseases.

Common neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's, are all associated with lipid peroxidation and iron. These diseases are caused by neurons dying from mechanisms involving iron accumulation, lipid peroxidation, and cell death by ferroptosis. The difference between these diseases may only be the location in the brain where the damage occurs and the trigger that initiates the process. 

Ferroptosis also plays an important role in the development of other conditions, such as acute kidney injury, ischemia/reperfusion injury, and cardiovascular disease.14 In a broad sense, if we slow or control ferroptosis, we may be able to slow or control these diseases.13 This may be done 2 ways: chelation of iron or the increase of antioxidants or other ferroptosis inhibitors within cells.15

Ferroptosis may also have an important a role in treating cancer. But here, its role is usually reversed. Ferroptosis is linked to both promotion and suppression of cancer. In many situations though, “the distinctive metabolism of cancer cells, their high load of reactive oxygen species (ROS) and their specific mutations render some of them intrinsically susceptible to ferroptosis, thereby exposing vulnerabilities that could be therapeutically targetable in certain cancer types.”16

Put simply, we may be able to use ferroptosis to kill cancer cells. In the right place with the right cancer, triggering and encouraging ferroptosis seems desirable. It is now understood that many cancer therapies, including radiation, chemotherapy, immunotherapy, and targeted therapies work in part by inducing ferroptosis.16 We’ve been using ferroptosis for years to treat cancer but just weren’t aware of it.

Tumors appear to seek ways to protect themselves from ferroptosis. Evolving ways to evade ferroptosis leads to tumor growth and development of what we describe as drug resistance. Finding drugs to prevent this evasion is a hot research topic as it is assumed that triggering ferroptosis or allowing it to go on uninhibited is a strategy for cancer treatment and a target for new cancer drugs.

On the other hand, the opposite approach might be taken in autoimmune diseases and particularly SLE.

Several substances inhibit ferroptosis from occurring. The best known is NAC, as it supplies cysteine and increases intracellular glutathione production, which puts the brakes on ferroptosis. Coenzyme Q10 (CoQ10) will also slow ferroptosis because it prevents lipid peroxidation. Recent studies have reported positive results from using CoQ10 in murine models of SLE.17,18

Polyunsaturated fatty acids (PUFAs) oxidize more readily than saturated or monounsaturated fatty acids, so increasing PUFAs within cells will increase ferroptosis, while increasing monounsaturated or saturated fatty acids will inhibit the process. Contrary to what we might guess, some data favor use of omega-3 PUFA–containing oils in SLE.19 Other studies do suggest extra virgin olive oil as beneficial for SLE.20,21 Mono-unsaturated oils suppress ferroptosis.22

That vitamin E discourages ferroptosis is a defining characteristic of this form of cell death. In SLE, vitamin E has been reported to reduce autoantibody production.23  Problems with iron uptake regulation occur in SLE,24 and iron chelation has been shown to reduce development of some SLE symptoms.25

If SLE is as tightly associated with ferroptosis as is now suspected, what is already known about inhibiting ferroptosis may be extrapolated to inform our treatment of SLE.  Avoiding what is known to stimulate ferroptosis might prevent a worsening of symptoms.

The deeper and, one hopes, longer-lasting message from these results is that they support a new theory that some autoimmune diseases, in particular SLE, are the result of ferroptosis and should be treated in this light.

Astralagus appears to inhibit ferroptosis. It prevents injury to lung tissue by PM2.5, and this protection is thought to be due to ferroptosis inhibition.26 So far, murine research suggests that astralagus may provide benefit in SLE.27

Several drugs and natural substances are known to encourage ferroptosis. These drugs, including sorafenib, sulfasalazine, and statins might aggravate SLE. Natural substances including artemisinin, withaferin A, and fenugreek encourage ferroptosis. While some may be useful adjuncts to cancer treatment, this should be a caution to SLE patients.  Withaferin A, coadministered with sorafenib, reduces drug resistance by increasing ferroptosis.28 Withaferin A is typically isolated from Withania somnifera, a botanical medicine familiar to and considered with favor by naturopathic doctors. 

Sulfasalazine, the drug used in treating ulcerative colitis, impedes cysteine transport into cells and so limits glutathione production. In doing so, it enhances ferroptosis. It is being tested to enhance treatment of endometrial cancer.29 Also, by inhibiting cystine transport and inducing ferroptosis, it reduces growth in fibrosarcoma and non-small-cell lung cancer.30

But in SLE, sulfasalazine may precipitate emergence or an aggravation of the disease. When this was first reported in 2012, the term ferroptosis had yet to be invented and at the time, the authors admitted, “The underlying mechanism by which 5-ASA/sulphasalazine induces SLE or lupus-like syndromes is not clear and high awareness for possible predictive factors is demanded for early prevention. In most cases the symptoms from drug-induced lupus have been reversible after the discontinuation of the drug.”31

Several common supplements appear to inhibit ferroptosis including berberine,32 melatonin (in diabetes),33,34 red clover,35 and quercetin.36 Whether these will have benefit in SLE is unclear. 

We might guess that exercise will help spur ferroptosis simply because of the increased production of reactive oxygen species. Exercise reliably creates reactive oxygen because the increased energy demands on cell mitochondria increases ROS production. While this sounds logical, no experimental data have been published confirming that exercise does increase ferroptosis.37 Exercise clearly improves cancer outcomes, but it’s not known if ferroptosis plays a role in that improvement. 

When it comes to SLE, a recent Cochrane style review of the literature wouldn’t commit to the idea that exercise provides any benefit in SLE: “The addition of exercise to usual pharmacological care may have little to no effect on fatigue, functional capacity, and disease activity (low-certainty evidence). We are uncertain whether the addition of exercise improves pain (very low-certainty evidence), or results in fewer or more withdrawals (very low-certainty evidence).38

Let’s add NAC to our SLE protocols and keep our attention on the possibly bigger picture that suggests a treatment strategy that accounts for effect on ferroptosis cell death may prove useful in a wide range of diseases in the future.

Categorized Under


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