Systemic lupus erythematosus combined with Wilson's disease: a case report and literature review.

BACKGROUND: Systemic lupus erythematosus (SLE) and Wilson's disease (WD) are both systemic diseases that can affect multiple organs in the body. The coexistence of SLE and WD is rarely encountered in clinical practice, making it challenging to diagnose. CASE REPORT: We present the case of a 9-year-old girl who initially presented with proteinuria, haematuria, pancytopenia, hypocomplementemia, and positivity for multiple autoantibodies. She was diagnosed with SLE, and her blood biochemistry showed elevated liver enzymes at the time of diagnosis. Despite effective control of her symptoms, her liver enzymes remained elevated during regular follow-up. Laboratory tests revealed decreased serum copper and ceruloplasmin levels, along with elevated urinary copper. Liver biopsy revealed chronic active hepatitis, moderate inflammation, moderate-severe fibrosis, and a trend towards local cirrhosis. Genetic sequencing revealed compound heterozygous mutations in the ATP7B gene, confirming the diagnosis of SLE with WD. The girl received treatment with a high-zinc/low-copper diet, but her liver function did not improve. Upon recommendation following multidisciplinary consultation, she underwent liver transplantation. Unfortunately, she passed away on the fourth day after the surgery. CONCLUSIONS: SLE and WD are diseases that involve multiple systems and organs in the body, and SLE complicated with WD is rarely encountered in the clinic; therefore, it is easy to misdiagnose. Because penicillamine can induce lupus, it is not recommended. Liver transplantation is indicated for patients with liver disease who do not respond to medical treatment with WD. However, further research is needed to determine the optimal timing of liver transplantation for patients with SLE complicated with WD.

Reduction of molecular oxygen in flavodiiron proteins - Catalytic mechanism and comparison to heme-copper oxidases.

The family of flavodiiron proteins (FDPs) plays an important role in the scavenging and detoxification of both molecular oxygen and nitric oxide. Using electrons from a flavin mononucleotide cofactor molecular oxygen is reduced to water and nitric oxide is reduced to nitrous oxide and water. While the mechanism for NO reduction in FDPs has been studied extensively, there is very little information available about O2 reduction. Here we use hybrid density functional theory (DFT) to study the mechanism for O2 reduction in FDPs. An important finding is that a proton coupled reduction is needed after the O2 molecule has bound to the diferrous diiron active site and before the OO bond can be cleaved. This is in contrast to the mechanism for NO reduction, where both NN bond formation and NO bond cleavage occurs from the same starting structure without any further reduction, according to both experimental and computational results. This computational result for the O2 reduction mechanism should be possible to evaluate experimentally. Another difference between the two substrates is that the actual OO bond cleavage barrier is low, and not involved in rate-limiting the reduction process, while the barrier connected with bond cleavage/formation in the NO reduction process is of similar height as the rate-limiting steps. We suggest that these results may be part of the explanation for the generally higher activity for O2 reduction as compared to NO reduction in most FDPs. Comparisons are also made to the O2 reduction reaction in the family of heme­copper oxidases.

Evidence for disrupted copper availability in human spinal cord supports CuII(atsm) as a treatment option for sporadic cases of ALS.

The copper compound CuII(atsm) has progressed to phase 2/3 testing for treatment of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). CuII(atsm) is neuroprotective in mutant SOD1 mouse models of ALS where its activity is ascribed in part to improving availability of essential copper. However, SOD1 mutations cause only ~ 2% of ALS cases and therapeutic relevance of copper availability in sporadic ALS is unresolved. Herein we assessed spinal cord tissue from human cases of sporadic ALS for copper-related changes. We found that when compared to control cases the natural distribution of spinal cord copper was disrupted in sporadic ALS. A standout feature was decreased copper levels in the ventral grey matter, the primary anatomical site of neuronal loss in ALS. Altered expression of genes involved in copper handling indicated disrupted copper availability, and this was evident in decreased copper-dependent ferroxidase activity despite increased abundance of the ferroxidases ceruloplasmin and hephaestin. Mice expressing mutant SOD1 recapitulate salient features of ALS and the unsatiated requirement for copper in these mice is a biochemical target for CuII(atsm). Our results from human spinal cord indicate a therapeutic mechanism of action for CuII(atsm) involving copper availability may also be pertinent to sporadic cases of ALS.

Tumor associated macrophages transfer ceruloplasmin mRNA to fibrosarcoma cells and protect them from ferroptosis.

Solid tumors are characterized by hypoxic areas, which are prone for macrophage infiltration. Once infiltrated, macrophages polarize to tumor associated macrophages (TAM) to support tumor progression. Therefore, the crosstalk between TAMs and tumor cells is of current interest for the development of novel therapeutic strategies. These may comprise induction of an iron- and lipid peroxidation-dependent form of cell death, known as ferroptosis. To study the macrophage - tumor cell crosstalk we polarized primary human macrophages towards a TAM-like phenotype, co-cultured them with HT1080 fibrosarcoma cells, and analyzed the tumor cell response to ferroptosis induction. In TAMs the expression of ceruloplasmin mRNA increased, which was driven by hypoxia inducible factor 2 and signal transducer and activator of transcription 1. Subsequently, ceruloplasmin mRNA was transferred from TAMs to HT1080 cells via extracellular vesicles. In tumor cells, mRNA was translated into protein to protect HT1080 cells from RSL3-induced ferroptosis. Mechanistically this was based on reduced iron abundance and lipid peroxidation. Interestingly, in naïve macrophages also hypoxia induced ceruloplasmin under hypoxia and a co-culture of HT1080 cells with hypoxic macrophages recapitulated the protective effect observed in TAM co-cultures. In conclusion, TAMs provoke tumor cells to release iron and thereby protect them from lipid peroxidation/ferroptosis.

The Ferroxidase Centre of Escherichia coli Bacterioferritin Plays a Key Role in the Reductive Mobilisation of the Mineral Iron Core.

Ferritins are multimeric cage-forming proteins that play a crucial role in cellular iron homeostasis. All H-chain-type ferritins harbour a diiron site, the ferroxidase centre, at the centre of a 4 α-helical bundle, but bacterioferritins are unique in also binding 12 hemes per 24 meric assembly. The ferroxidase centre is known to be required for the rapid oxidation of Fe2+ during deposition of an immobilised ferric mineral core within the protein's hollow interior. In contrast, the heme of bacterioferritin is required for the efficient reduction of the mineral core during iron release, but has little effect on the rate of either oxidation or mineralisation of iron. Thus, the current view is that these two cofactors function in iron uptake and release, respectively, with no functional overlap. However, rapid electron transfer between the heme and ferroxidase centre of bacterioferritin from Escherichia coli was recently demonstrated, suggesting that the two cofactors may be functionally connected. Here we report absorbance and (magnetic) circular dichroism spectroscopies, together with in vitro assays of iron-release kinetics, which demonstrate that the ferroxidase centre plays an important role in the reductive mobilisation of the bacterioferritin mineral core, which is dependent on the heme-ferroxidase centre electron transfer pathway.

Novel LncRNA LINC02936 Suppresses Ferroptosis and Promotes Tumor Progression by Interacting with SIX1/CP Axis in Endometrial Cancer.

Endometrial cancer (EC) is a prevalent gynecological malignancy, and metabolic disorders are among its most significant risk factors. Abnormal iron metabolism is associated with the progression of cancer malignancy. Nevertheless, the involvement of iron metabolism in the EC remains uncertain. Ceruloplasmin (CP) functions as a multicopper oxidase and ferroxidase, playing a crucial role in maintaining the metabolic balance between copper and iron. Prior research has demonstrated that the dysregulated expression of CP has important clinical implications in EC. However, ​the specific underlying molecular mechanisms remains uncertain. This research examined the impact of CP on the malignant advancement of EC by suppressing ferroptosis. Next, we explored the possibility that Long non-coding RNA (lncRNA) LINC02936/SIX1/CP axis may be a key pathway for inhibiting ferroptosis and promoting cancer progression in EC. Mechanistically, SIX1 modulates the expression of CP, whereas LINC02936 interacts with SIX1 and recruits SIX1 to the CP promoter, leading to upregulation of CP, inhibition of ferroptosis, and promotion of EC progression. Administration of a small peptide cloud block the LINC02936-SIX1 interaction, thereby inhibits EC progression by promoting ferroptosis. Altogether, this is the first report on the lncRNA regulation of ferroptosis in EC. Our research enhances the knowledge of the lncRNA-mediated regulation of ferroptosis in EC progression and indicates the potential therapeutic significance of the LINC02936/SIX1/CP axis in treating EC.

Structural Insights into the Reaction between Hydrogen Peroxide and Di-iron Complexes at the Ferroxidase Center of Ferritin.

The Fe(II) oxidation mechanism in the ferroxidase center of heavy chain ferritin has been studied extensively. However, the actual production of H2O2 was found to be substantially lower than expected at low flux of Fe(II) to ferritin subunits. Here, we demonstrated that H2O2 could interact with the di-iron nuclear center, leading to the production of hydroxyl radicals and oxygen. Two reaction intermediates were captured in the ferroxidase center by using the time-lapse crystallographic techniques in a shellfish ferritin. The crystal structures revealed the binding of H2O2 as a µ -1,2-peroxo-diferric species and the binding of O2 to the diferric structure. This investigation sheds light on the reaction between the di-iron nuclear center and H2O2 and provides insights for the exploitation of metalloenzymes.

New orphan disease therapies from the proteome of industrial plasma processing waste- a treatment for aceruloplasminemia.

Plasma-derived therapeutic proteins are produced through an industrial fractionation process where proteins are purified from individual intermediates, some of which remain unused and are discarded. Relatively few plasma-derived proteins are exploited clinically, with most of available plasma being directed towards the manufacture of immunoglobulin and albumin. Although the plasma proteome provides opportunities to develop novel protein replacement therapies, particularly for rare diseases, the high cost of plasma together with small patient populations impact negatively on the development of plasma-derived orphan drugs. Enabling therapeutics development from unused plasma fractionation intermediates would therefore constitute a substantial innovation. To this objective, we characterized the proteome of unused plasma fractionation intermediates and prioritized proteins for their potential as new candidate therapies for human disease. We selected ceruloplasmin, a plasma ferroxidase, as a potential therapy for aceruloplasminemia, an adult-onset ultra-rare neurological disease caused by iron accumulation as a result of ceruloplasmin mutations. Intraperitoneally administered ceruloplasmin, purified from an unused plasma fractionation intermediate, was able to prevent neurological, hepatic and hematological phenotypes in ceruloplasmin-deficient mice. These data demonstrate the feasibility of transforming industrial waste plasma fraction into a raw material for manufacturing of new candidate proteins for replacement therapies, optimizing plasma use and reducing waste generation.

SOD1-Related Cerebellar Ataxia and Motor Neuron Disease: Cp Variant as Functional Modifier?

We describe a novel superoxide dismutase (SOD1) mutation-associated clinical phenotype of cerebellar ataxia and motor neuron disease with a variant in the ceruloplasmin (Cp) gene, which may have possibly contributed to a multi-factorial phenotype, supported by genetic and protein structure analyses.

Variations in Blood Copper and Possible Mechanisms During Pregnancy.

Copper (Cu), an essential trace element, is crucial for both the mother and fetus. Currently, an increasing number of studies have focused on blood copper levels during pregnancy. Studies have found that blood copper levels in pregnant women are higher than those in reproductive-age women, but the trend, mainly in the 2nd and 3rd trimester, is still controversial. Most studies showed that blood copper levels gradually increased during pregnancy, while some studies found that blood copper levels remained stable or even decreased in the 3rd trimester. The possible mechanisms of variations in blood copper during pregnancy include the influence of estrogen (hepatic uptake and excretion, ceruloplasmin synthesis, maternal-fetal transport, etc.), the interaction of other trace elements (Fe, Zn, etc.) and other factors. Among them, maternal-fetal copper transport caused by elevated estrogen may be the main reason for the inconsistencies observed in the 2nd and 3rd trimester during pregnancy. However, there are some mechanisms require further investigation. In the future, the trend and mechanisms of blood copper during pregnancy should be explored more deeply to help doctors better monitor copper status and detect copper abnormalities in time.

Evaluation of the dynamic thiol/disulfide homeostasis in patients with chronic venous insufficiency.

OBJECTIVE: There is no study in the literature evaluating the dynamic thiol/disulfide homeostasis in patients with chronic venous insufficiency. Thus, we designed this study to evaluate the dynamic thiol/disulfide homeostasis as a novel indicator of oxidative stress in patients with chronic venous insufficiency. METHODS: This was a prospective case-control study performed at the department of cardiovascular surgery of a tertiary referral hospital in Turkey. A total of 80 (CEAP C3-C6) patients with lower extremity chronic venous insufficiency (as the study group) and 80 healthy subjects (as the control group) were enrolled to the study. The participants' basic demographic and clinical characteristics as well as serum levels of some laboratory parameters including albumin, ferroxidase, myeloperoxidase, native thiol, total thiol, disulphide, native thiol/total thiol, disulphide/native thiol, and disulphide/total thiol were determined, and then compared between the groups. RESULTS: In terms of basic demographic and clinical characteristics, both groups were statistically similar, and there were no significant differences between the groups. When the laboratory parameters were considered, serum ferroxidase and myeloperoxidase levels were detected to be significantly higher, whereas albumin, native thiol, total thiol, and disulphide levels were detected to be significantly lower in the study group than in the control group. CONCLUSIONS: Dynamic thiol/disulphide homeostasis could be considered as an indicator reflecting the oxidative stress status in patients with chronic venous insufficiency.

Lipid dysmetabolism in ceruloplasmin-deficient mice revealed both in vivo and ex vivo by MRI, MRS and NMR analyses.

Ceruloplasmin (Cp) is a ferroxidase that plays a role in cellular iron homeostasis and is mainly expressed in the liver and secreted into the blood. Cp is also produced by adipose tissue, which releases it as an adipokine. Although a dysfunctional interaction of iron with the metabolism of lipids has been associated with several metabolic diseases, the role of Cp in adipose tissue metabolism and in the interplay between hepatocytes and adipocytes has been poorly investigated. We previously found that Cp-deficient (CpKO) mice become overweight and demonstrate adipose tissue accumulation together with liver steatosis during aging, suggestive of lipid dysmetabolism. In the present study, we investigated the lipid alterations which occur during aging in adipose tissue and liver of CpKO and wild-type mice both in vivo and ex vivo. During aging of CpKO mice, we observed adipose tissue accumulation and liver lipid deposition, both of which are associated with macrophage infiltration. Liver lipid deposition was characterized by accumulation of triglycerides, fatty acids and ω-3 fatty acids, as well as by a switch from unsaturated to saturated fatty acids, which is characteristic of lipid storage. Liver steatosis was preceded by iron deposition and macrophage infiltration, and this was observed to be already occurring in younger CpKO mice. The accumulation of ω-3 fatty acids, which can only be acquired through diet, was associated with body weight increase in CpKO mice despite food intake being equal to that of wild-type mice, thus underlining the alterations in lipid metabolism/catabolism in Cp-deficient animals.

Sepsis induced cardiotoxicity by promoting cardiomyocyte cuproptosis.

BACKGROUND: Currently, sepsis induced cardiotoxicity is among the major causes of sepsis-related death. The specific molecular mechanisms of sepsis induced cardiotoxicity are currently unknown. Therefore, the purpose of this paper is to identify the key molecule mechanisms for sepsis induced cardiotoxicity. METHODS: Original data of sepsis induced cardiotoxicity was derived from Gene Expression Omnibus (GEO; GSE63920; GSE44363; GSE159309) dataset. Functional enrichment analysis was used to analysis sepsis induced cardiotoxicity related signaling pathways. Our findings also have explored the relationship of cuproptosis and N6-Methyladenosine (m6A) in sepsis induced cardiotoxicity. Mice are randomly assigned to 3 groups: saline treatment control group, LPS group administered a single 5 mg/kg dose of LPS for 24 h, LPS + CD274 inhibitor group administered 10 mg/kg CD274 inhibitor for 24 h. RESULTS: Overall, expression of cuproptosis-related genes (CRGs) CD274, Ceruloplasmin (CP), Vascular endothelial growth factor A (VEGFA), Copper chaperone for cytochrome c oxidase 11 (COX11), chemokine C-C motif ligand 8 (CCL8), Mitogen-activated protein kinase kinase 1(MAP2K1), Amine oxidase 3 (AOC3) were significantly altered in sepsis induced cardiotoxicity. The results of spearman correlation analysis was significant relationship between differentially regulated genes (DEGs) of CRGs and the expression level of m6A methylation genes. GO and KEGG showed that these genes were enriched in response to interferon-beta, MHC class I peptide loading complex, proteasome core complex, chemokine receptor binding, TAP binding, chemokine activity, cytokine activity and many more. These findings suggest that cuproptosis is strongly associated with sepsis induced cardiotoxicity. CONCLUSION: In the present study, we found that cuproptosis were associated with sepsis induced cardiotoxicity. The CD274, CP, VEGFA, COX11, CCL8, MAP2K1, AOC3 genes are showing a significant difference expression in sepsis induced cardiotoxicity. Our studies have found significant correlations between CRGs and m6A methylation related genes in sepsis induced cardiotoxicity. These results provide insight into mechanism for sepsis induced cardiotoxicity.

Observational study on the associations between milk yield, composition, and coagulation properties with blood biomarkers of health in Holstein cows.

The considerable increase in the production capacity of individual cows owing to both selective breeding and innovations in the dairy sector has posed challenges to management practices in terms of maintaining the nutritional and metabolic health status of dairy cows. In this observational study, we investigated the associations between milk yield, composition, and technological traits and a set of 21 blood biomarkers related to energy metabolism, liver function or hepatic damage, oxidative stress, and inflammation or innate immunity in a population of 1,369 high-yielding Holstein-Friesian dairy cows. The milk traits investigated in this study included 4 production traits (milk yield, fat yield, protein yield, daily milk energy output), 5 traits related to milk composition (fat, protein, casein, and lactose percentages and urea), 11 milk technological traits (5 milk coagulation properties and 6 curd-firming traits). All milk traits (i.e., production, composition, and technological traits) were analyzed according to a linear mixed model that included the days in milk, the parity order, and the blood metabolites (tested one at a time) as fixed effects and the herd and date of sampling as random effects. Our findings revealed that milk yield and daily milk energy output were positively and linearly associated with total cholesterol, nonesterified fatty acids, urea, aspartate aminotransferase, γ-glutamyl transferase, total bilirubin, albumin, and ferric-reducing antioxidant power, whereas they were negatively associated with glucose, creatinine, alkaline phosphatase, total reactive oxygen metabolites, and proinflammatory proteins (ceruloplasmin, haptoglobin, and myeloperoxidase). Regarding composition traits, the protein percentage was negatively associated with nonesterified fatty acids and ß-hydroxybutyrate (BHB), while the fat percentage was positively associated with BHB, and negatively associated with paraoxonase. Moreover, we found that the lactose percentage increased with increasing cholesterol and albumin and decreased with increasing ceruloplasmin, haptoglobin, and myeloperoxidase. Milk urea increased with an increase in cholesterol, blood urea, nonesterified fatty acids, and BHB, and decreased with an increase in proinflammatory proteins. Finally, no association was found between the blood metabolites and milk coagulation properties and curd-firming traits. In conclusion, this study showed that variations in blood metabolites had strong associations with milk productivity traits, the lactose percentage, and milk urea, but no relationships with technological traits of milk. Specifically, increasing levels of proinflammatory and oxidative stress metabolites, such as ceruloplasmin, haptoglobin, myeloperoxidase, and total reactive oxygen metabolites, were shown to be associated with reductions in milk yield, daily milk energy output, lactose percentage, and milk urea. These results highlight the close connection between the metabolic and innate immunity status and production performance. This connection is not limited to specific clinical diseases or to the transition phase but manifests throughout the entire lactation. These outcomes emphasize the importance of identifying cows with subacute inflammatory and oxidative stress as a means of reducing metabolic impairments and avoiding milk fluctuations.

Ceruloplasmin Reduces the Lactoferrin/Oleic Acid Antitumor Complex-Mediated Release of Heme-Containing Proteins from Blood Cells.

Our previous study showed that not only bovine lactoferrin (LF), the protein of milk and neutrophils, but also the human species forms complexes with oleic acid (OA) that inhibit tumor growth. Repeated injections of human LF in complex with OA (LF/8OA) to hepatoma-carrying mice decelerated tumor growth and increased animals' longevity. However, whether the effect of the LF/8OA complex is directed exclusively against malignant cells was not studied. Hence, its effect on normal blood cells was assayed, along with its possible modulation of ceruloplasmin (CP), the preferred partner of LF among plasma proteins. The complex LF/8OA (6 µM) caused hemolysis, unlike LF alone or BSA/8OA (250 µM). The activation of neutrophils with exocytosis of myeloperoxidase (MPO), a potent oxidant, was induced by 1 µM LF/8OA, whereas BSA/8OA had a similar effect at a concentration increased by an order. The egress of heme-containing proteins, i.e., MPO and hemoglobin, from blood cells affected by LF/8OA was followed by a pronounced oxidative/halogenating stress. CP, which is the natural inhibitor of MPO, added at a concentration of 2 mol per 1 mol of LF/8OA abrogated its cytotoxic effect. It seems likely that CP can be used effectively in regulating the LF/8OA complex's antitumor activity.

Investigation of the Mechanism of Membrane Potential Generation by Heme-Copper Respiratory Oxidases in a Real Time Mode.

Heme-copper respiratory oxidases are highly efficient molecular machines. These membrane enzymes catalyze the final step of cellular respiration in eukaryotes and many prokaryotes: the transfer of electrons from cytochromes or quinols to molecular oxygen and oxygen reduction to water. The free energy released in this redox reaction is converted by heme-copper respiratory oxidases into the transmembrane gradient of the electrochemical potential of hydrogen ions H+). Heme-copper respiratory oxidases have a unique mechanism for generating H+, namely, a redox-coupled proton pump. A combination of direct electrometric method for measuring the kinetics of membrane potential generation with the methods of prestationary kinetics and site-directed mutagenesis in the studies of heme-copper oxidases allows to obtain a unique information on the translocation of protons inside the proteins in real time. The review summarizes the data of studies employing time-resolved electrometry to decipher the mechanisms of functioning of these important bioenergetic enzymes.

Correlation Between Substantia Nigra Hyperechogenicity and Iron Metabolism in the Postural Instability Gait Difficulty Subtype of Parkinson's Disease.

OBJECTIVE: The correlation between substantia nigra (SN) hyperechogenicity on transcranial sonography (TCS) and serum iron metabolism parameters in patients with the postural instability gait difficulty (PIGD) subtype of Parkinson's disease (PD) was investigated so as to explore the pathological mechanism of SN hyperechogenicity. METHODS: The study enrolled 95 PIGD patients recruited by the Parkinson's Disease Specialty in the Second Affiliated Hospital of Soochow University during June 2019-2021. On the basis of the TCS results, the PIGD patients were assigned to the PD with SN hyperechogenicity (SN+) group (n = 60) and PD without SN hyperechogenicity (SN-) group (n = 35). Meanwhile, 49 sex- and age-matched healthy individuals were included in the control group. All participants underwent blood tests. Differences in the iron metabolism parameters among the three groups and the correlation between SN hyperechogenicity and serum iron metabolism parameters were analyzed. RESULTS: Serum ferritin, ceruloplasmin and transferrin levels were lower in the SN+ and SN- groups than in the control group (all p values <0.001). The serum ceruloplasmin level was lower in the SN+ group (0.23 [0.20, 0.25] g/L) than in the SN- group (0.25 [0.22, 0.29] g/L) (p = 0.001), and the proportion of patients with an abnormal ceruloplasmin level was higher in the SN+ group than in the SN- group (43.3% [26/60] vs. 14.3% [5/35], χ2 = 8.484, p = 0.004). Moreover, the SN hyperechogenicity area was negatively correlated with the serum transferrin level (r = -0.428, p < 0.001). CONCLUSION: Decreased serum ceruloplasmin levels may be associated with SN hyperechogenicity development in PIGD patients. The SN hyperechogenicity area is negatively correlated with the serum transferrin level.

Ferroptosis-related factors in the substantia nigra are associated with Parkinson's disease.

Ferroptosis is an iron-dependent, lipid peroxidation-driven cell death pathway, while Parkinson's disease (PD) patients exhibit iron deposition and lipid peroxidation in the brain. Thus, the features of ferroptosis highly overlap with the pathophysiological features of PD. Despite this superficial connection, the possible role(s) of ferroptosis-related (Fr) proteins in dopaminergic neurons and/or glial cells in the substantia nigra (SN) in PD have not been examined in depth. To explore the correlations between the different SN cell types and ferroptosis at the single-cell level in PD patients, and to explore genes that may affect the sensitivity of dopaminergic neurons to ferroptosis, we performed in silico analysis of a single cell RNA sequence (RNA-seq) set (GSE178265) from the Gene Expression Omnibus (GEO) database. We identified differentially expressed genes (DEGs) in the different cell types in the human SN, and proceeded to perform enrichment analysis, constructing a protein-protein interaction network from the DEGs of dopaminergic neurons with the Metascape database. We examined the intersection of Fr genes present in the FerrDb database with DEGs from the GSE178265 set to identify Fr-DEGs in the different brain cells. Further, we identified Fr-DEGs encoding secreted proteins to implicate cell-cell interactions in the potential stimulation of ferroptosis in PD. The Fr-DEGs we identified were verified using the bulk RNA-seq sets (GSE49036 and GSE20164). The number of dopaminergic neurons decreased in the SN of PD patients. Interestingly, non-dopaminergic neurons possessed the fewest DEGs. Enrichment analysis of dopaminergic neurons' DEGs revealed changes in transmission across chemical synapses and ATP metabolic process in PD. The secreted Fr-DEGs identified were ceruloplasmin (CP), high mobility group box 1 (HMGB1) and transferrin (TF). The bulk RNA-seq set from the GEO database demonstrates that CP expression is increased in the PD brain. In conclusion, our results identify CP as a potential therapeutic target to protect dopaminergic neurons by reducing neurons' sensitivity to ferroptosis.