Parathyroid hormone (PTH) promotes bone catabolism by targeting bone marrow (BM) stromal cells (SCs) and their osteoblastic progeny. Here we show that a continuous infusion of PTH that mimics hyperparathyroidism fails to induce osteoclast formation, bone resorption, and cortical bone loss in mice lacking T cells. T cells provide proliferative and survival cues to SCs and sensitize SCs to PTH through CD40 ligand (CD40L), a surface molecule of activated T cells that induces CD40 signaling in SCs. As a result, deletion of T cells or T cell-expressed CD40L blunts the bone catabolic activity of PTH by decreasing bone marrow SC number, the receptor activator of nuclear factor-kappaB ligand (RANKL)/OSTEOPROTEGERN (OPG) ratio, and osteoclastogenic activity. Therefore, T cells play an essential permissive role in hyperparathyroidism as they influence SC proliferation, life span, and function through CD40L. T cell-SC crosstalk pathways may thus provide pharmacological targets for PTH-induced bone disease.

The goal of the current study is to examine the biological effects of epithelial-specific tumor suppressor maspin on tumor host immune response. Accumulated evidence demonstrates an anti-tumor effect of maspin on tumor growth, invasion and metastasis. The molecular mechanism underlying these biological functions of maspin is thought to be through histone deacetylase inhibition, key to the maintenance of differentiated epithelial phenotype. Since tumor-driven stromal reactivities co-evolve in tumor progression and metastasis, it is not surprising that maspin expression in tumor cells inhibits extracellular matrix degradation, increases fibrosis and blocks hypoxia-induced angiogenesis. Using the athymic nude mouse model capable of supporting the growth and progression of xenogeneic human prostate cancer cells, we further demonstrate that maspin expression in tumor cells elicits neutrophil- and B cells-dependent host tumor immunogenicity. Specifically, mice bearing maspin-expressing tumors exhibited increased systemic and intratumoral neutrophil maturation, activation and antibody-dependent cytotoxicity, and decreased peritumoral lymphangiogenesis. These results reveal a novel biological function of maspin in directing host immunity towards tumor elimination that helps explain the significant reduction of xenograft tumor incidence in vivo and the clinical correlation of maspin with better prognosis of several types of cancer. Taken together, our data raised the possibility for novel maspin-based cancer immunotherapies.

Vitiligo is an autoimmune disease in which depigmented skin results from the destruction of melanocytes, with epidemiological association with other autoimmune diseases. In previous linkage and genome-wide association studies (GWAS1 and GWAS2), we identified 27 vitiligo susceptibility loci in patients of European ancestry. We carried out a third GWAS (GWAS3) in European-ancestry subjects, with augmented GWAS1 and GWAS2 controls, genome-wide imputation, and meta-analysis of all three GWAS, followed by an independent replication. The combined analyses, with 4,680 cases and 39,586 controls, identified 23 new significantly associated loci and 7 suggestive loci. Most encode immune and apoptotic regulators, with some also associated with other autoimmune diseases, as well as several melanocyte regulators. Bioinformatic analyses indicate a predominance of causal regulatory variation, some of which corresponds to expression quantitative trait loci (eQTLs) at these loci. Together, the identified genes provide a framework for the genetic architecture and pathobiology of vitiligo, highlight relationships with other autoimmune diseases and melanoma, and offer potential targets for treatment.

Nuclear receptor coactivator 3 (NCOA3) is a transcriptional coactivator that has elevated expression in multiple tumor types, including colorectal cancer (CRC). However, the molecular mechanisms that regulate the tumorigenic functions of NCOA3 in CRC remain largely unknown. In this study, we aimed to discover and identify the novel regulatory proteins of NCOA3 and explore their mechanisms of action. Immunoprecipitation (IP) coupled with mass spectrometry (IP-MS) analysis was used to detect, identify, and verify the proteins that interacted with NCOA3 in CRC cells. The biological functions of the candidate proteins and the underlying molecular mechanism were investigated in CRC cells and mouse model in vitro and in vivo. The clinical significance of NCOA3 and its interaction partner protein in CRC patients was also studied. We identified mitotic arrest deficient 2-like protein 2 (MAD2L2, also known as MAD2B or REV7), with two signal peptide sequences of LIPLK and EVYPVGIFQK, to be an interaction partner of NCOA3. Overexpression of MAD2L2 suppressed the proliferation, migration, and clonogenicity of CRC cells by inducing the degradation of NCOA3. The mechanism study showed that increased MAD2L2 expression in CRC cells activated p38, which was required for the phosphorylation of NCOA3 that led to its ubiquitination and degradation by the proteasome. Moreover, we found that MAD2L2 predicted favorable prognosis in CRC patients. We have discovered a novel role of MAD2L2 in the regulation of NCOA3 degradation and proposed that MAD2L2 serves as a tumor suppressor in CRC.

We observe and analyze multiple Fano resonances and the plasmon-induced transparency (PIT) arising from waveguidecoupled surface plasmon resonance in a metal-dielectric Kretschmann configuration. It is shown that the simulation results for designed structures agree well with those of the dispersion relation of waveguide theory. We demonstrate that the coupling between the surface plasmon polariton mode and multi-order planar waveguide modes leads to multiple Fano resonances and PIT. The obtained results show that the number of Fano resonances and the linewidth of resonances depend on two structural parameters, the Parylene C and SiO2 layers, respectively. For the sensing action of Fano resonance, the figure of merit for the sensitivity by intensity is estimated to be 44 times higher than that of conventional surface plasmon resonance sensors. Our research reveals the potential advantage of sensors with high sensitivity based on coupling between the SPP mode and multi-order PWG modes.

Epidermal Langerhans cells (LCs) are skin-resident dendritic cells that are essential for the induction of skin immunity and tolerance. Transforming growth factor-β 1 (TGFβ1) is a crucial factor for LC maintenance and function. However, the underlying TGFβ1 signaling pathways remain unclear. Our previous research has shown that the TGFβ1/Smad3 signaling pathway does not impact LC homeostasis and maturation. In this study, we generated mice with conditional deletions of either individual Smad2, Smad4, or both Smad2 and Smad4 in the LC lineage or myeloid lineage, to further explore the impact of TGFβ1/Smad signaling pathways on LCs. We found that interruption of Smad2 or Smad4 individually or simultaneously in the LC lineage did not significantly impact the maintenance, maturation, antigen uptake, and migration of LCs in vivo or in vitro during steady state. However, the interruption of both Smad2 and Smad4 pathways in the myeloid lineage led to a dramatic inhibition of bone marrow-derived LCs in the inflammatory state. Overall, our data suggest that canonical TGFβ1/Smad2/4 signaling pathways are dispensable for epidermal LC homeostasis and maturation at steady state, but are critical for the long-term LC repopulation directly originating from the bone marrow in the inflammatory state.

T cell acute lymphoblastic leukemia (T-ALL) is commonly associated with activating mutations in the NOTCH1 pathway. Recent reports have shown a link between NOTCH1 signaling and intracellular Ca2+ homeostasis in T-ALL. Here, we investigate the role of store-operated Ca2+ entry (SOCE) mediated by the Ca2+ channel ORAI1 and its activators STIM1 and STIM2 in T-ALL. Deletion of STIM1 and STIM2 in leukemic cells abolishes SOCE and significantly prolongs the survival of mice in a NOTCH1-dependent model of T-ALL. The survival advantage is unrelated to the leukemic cell burden but is associated with the SOCE-dependent ability of malignant T lymphoblasts to cause inflammation in leukemia-infiltrated organs. Mice with STIM1/STIM2-deficient T-ALL show a markedly reduced necroinflammatory response in leukemia-infiltrated organs and downregulation of signaling pathways previously linked to cancer-induced inflammation. Our study shows that leukemic T lymphoblasts cause inflammation of leukemia-infiltrated organs that is dependent on SOCE.

The COVID-19 pandemic caused by the novel SARS-CoV-2 is more contagious than other coronaviruses and has higher rates of mortality than influenza. Identification of effective therapeutics is a crucial tool to treat those infected with SARS-CoV-2 and limit the spread of this novel disease globally. We deployed a bioinformatics workflow to identify candidate drugs for the treatment of COVID-19. Using an "omics" repository, the Library of Integrated Network-Based Cellular Signatures (LINCS), we simultaneously probed transcriptomic signatures of putative COVID-19 drugs and publicly available SARS-CoV-2 infected cell lines to identify novel therapeutics. We identified a shortlist of 20 candidate drugs: 8 are already under trial for the treatment of COVID-19, the remaining 12 have antiviral properties and 6 have antiviral efficacy against coronaviruses specifically, in vitro. All candidate drugs are either FDA approved or are under investigation. Our candidate drug findings are discordant with (i.e., reverse) SARS-CoV-2 transcriptome signatures generated in vitro, and a subset are also identified in transcriptome signatures generated from COVID-19 patient samples, like the MEK inhibitor selumetinib. Overall, our findings provide additional support for drugs that are already being explored as therapeutic agents for the treatment of COVID-19 and identify promising novel targets that are worthy of further investigation.

The development of invariant natural killer T (iNKT) cells requires a well-attuned set of transcription factors, but how these factors are regulated and coordinated remains poorly understood. MicroRNA-155 (miR-155) is a key regulator of numerous cellular processes that affects cell development and homeostasis. Here, we found that miR-155 was highly expressed in early iNKT cells upon thymic selection, and then its expression is gradually downregulated during iNKT cell development. However, the mice with miR-155 germline deletion had normal iNKT cell development. To address if downregulated miR-155 is required for iNKT cell development, we made a CD4Cre.miR-155 knock-in (KI) mouse model with miR-155 conditional overexpression in the T cell lineage. Upregulated miR-155 led to interruption of iNKT cell development, diminished iNKT17 and iNKT1 cells, augmented iNKT2 cells, and these defects were cell intrinsic. Furthermore, defective iNKT cells in miR-155KI mice resulted in the secondary innate-like CD8 T cell development. Mechanistically, miR-155 modulated multiple targets and signaling pathways to fine tune iNKT cell development. MiR-155 modulated Jarid2, a critical component of a histone modification complex, and Tab2, the upstream activation kinase complex component of NF-κB, which function additively in iNKT development and in promoting balanced iNKT1/iNKT2 differentiation. In addition, miR-155 also targeted Rictor, a signature component of mTORC2 that controls iNKT17 differentiation. Taken together, our results indicate that miR-155 serves as a key epigenetic regulator, coordinating multiple signaling pathways and transcriptional programs to precisely regulate iNKT cell development and functional lineage, as well as secondary innate CD8 T cell development.

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that develop in the thymus through three maturation stages to acquire effector function and differentiate into MAIT1 (T-bet+) and MAIT17 (RORγt+) subsets. Upon activation, MAIT cells release IFN-γ and IL-17, which modulate a broad spectrum of diseases. Recent studies indicate defective MAIT cell development in microRNA deficient mice, however, few individual miRNAs have been identified to regulate MAIT cells. MicroRNA-155 (miR-155) is a key regulator of numerous cellular processes that affect some immune cell development, but its role in MAIT cell development remains unclear. To address whether miR-155 is required for MAIT cell development, we performed gain-of-function and loss-of-function studies. We first generated a CD4Cre.miR-155 knock-in mouse model, in which miR-155 is over-expressed in the T cell lineage. We found that overexpression of miR-155 significantly reduced numbers and frequencies of MAIT cells in all immune organs and lungs and blocked thymic MAIT cell maturation through downregulating PLZF expression. Strikingly, upregulated miR-155 promoted MAIT1 differentiation and blocked MAIT17 differentiation, and timely inducible expression of miR-155 functionally inhibited peripheral MAIT cells secreting IL-17. miR-155 overexpression also increased CD4-CD8+ subset and decreased CD4-CD8- subset of MAIT cells. We further analyzed MAIT cells in conventional miR-155 knockout mice and found that lack of miR-155 also promoted MAIT1 differentiation and blocked MAIT17 differentiation but without alteration of their overall frequency, maturation and function. Overall, our results indicate that adequate miR-155 expression is required for normal MAIT1 and MAIT17 cell development and function.

The current severe situation of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has not been reversed and posed great threats to global health. Therefore, there is an urgent need to find out effective antiviral drugs. The 3-chymotrypsin-like protease (3CLpro) in SARS-CoV-2 serve as a promising anti-virus target due to its essential role in the regulation of virus reproduction. Here, we report an improved integrated approach to identify effective 3CLpro inhibitors from effective Chinese herbal formulas. With this approach, we identified the 5 natural products (NPs) including narcissoside, kaempferol-3-O-gentiobioside, rutin, vicenin-2 and isoschaftoside as potential anti-SARS-CoV-2 candidates. Subsequent molecular dynamics simulation additionally revealed that these molecules can be tightly bound to 3CLpro and confirmed effectiveness against COVID-19. Moreover, kaempferol-3-o-gentiobioside, vicenin-2 and isoschaftoside were first reported to have SARS-CoV-2 3CLpro inhibitory activity. In summary, this optimized integrated strategy for drug screening can be utilized in the discovery of antiviral drugs to achieve rapid acquisition of drugs with specific effects on antiviral targets.

While the pathophysiology of schizophrenia has been extensively investigated using homogenized postmortem brain samples, few studies have examined changes in brain samples with techniques that may attribute perturbations to specific cell types. To fill this gap, we performed microarray assays on mRNA isolated from anterior cingulate cortex (ACC) superficial and deep pyramidal neurons from 12 schizophrenia and 12 control subjects using laser-capture microdissection. Among all the annotated genes, we identified 134 significantly increased and 130 decreased genes in superficial pyramidal neurons, while 93 significantly increased and 101 decreased genes were found in deep pyramidal neurons, in schizophrenia compared to control subjects. In these differentially expressed genes, we detected lamina-specific changes of 55 and 31 genes in superficial and deep neurons in schizophrenia, respectively. Gene set enrichment analysis (GSEA) was applied to the entire pre-ranked differential expression gene lists to gain a complete pathway analysis throughout all annotated genes. Our analysis revealed overrepresented groups of gene sets in schizophrenia, particularly in immunity and synapse-related pathways, suggesting the disruption of these pathways plays an important role in schizophrenia. We also detected other pathways previously demonstrated in schizophrenia pathophysiology, including cytokine and chemotaxis, postsynaptic signaling, and glutamatergic synapses. In addition, we observed several novel pathways, including ubiquitin-independent protein catabolic process. Considering the effects of antipsychotic treatment on gene expression, we applied a novel bioinformatics approach to compare our differential expression gene profiles with 51 antipsychotic treatment datasets, demonstrating that our results were not influenced by antipsychotic treatment. Taken together, we found pyramidal neuron-specific changes in neuronal immunity, synaptic dysfunction, and olfactory dysregulation in schizophrenia, providing new insights for the cell-subtype specific pathophysiology of chronic schizophrenia.

Paeonia lactiflora Pall. (Paeonia) has aroused many concerns due to its extensive medicinal value, in which monoterpene glucoside paeoniflorin and its derivatives are the active chemical components. However, little is known in the molecular mechanism of monoterpenoids biosynthesis, and the regulation network between small RNAs and mRNAs in monoterpenoids biosynthesis has not been investigated yet. Herein, we attempted to reveal the tissue-specific regulation network of miRNAs and their targets related to paeoniaflorin and monoterpenoids biosynthesis in Paeonia by combining mRNA and miRNA expression data with degradome analysis. In all, 289 miRNAs and 30177 unigenes were identified, of which nine miRNAs from seven miRNA families including miR396, miR393, miR835, miR1144, miR3638, miR5794 and miR9555 were verified as monoterpenoids biosynthesis-related miRNAs by degradome sequencing. Moreover, the co-expression network analysis showed that four monoterpenoids-regulating TFs, namely AP2, MYBC1, SPL12 and TCP2, were putatively regulated by five miRNAs including miR172, miR828, miR858, miR156 and miR319, respectively. The present study will improve our knowledge of the molecular mechanisms of the paeoniaflorin and monoterpenoids biosynthesis mediated by miRNA to a new level, and provide a valuable resource for further study on Paeonia.

Animal models have expanded our understanding of temporal lobe epilepsy (TLE). However, translating these to cell-specific druggable hypotheses is not explored. Herein, we conducted an integrative insilico-analysis of an available transcriptomics dataset obtained from animals with pilocarpine-induced-TLE. A set of 119 genes with subtle-to-moderate impact predicted most forms of epilepsy with ~ 97% accuracy and characteristically mapped to upregulated homeostatic and downregulated synaptic pathways. The deconvolution of cellular proportions revealed opposing changes in diverse cell types. The proportion of nonneuronal cells increased whereas that of interneurons, except for those expressing vasoactive intestinal peptide (Vip), decreased, and pyramidal neurons of the cornu-ammonis (CA) subfields showed the highest variation in proportion. A probabilistic Bayesian-network demonstrated an aberrant and oscillating physiological interaction between nonneuronal cells involved in the blood-brain-barrier and Vip interneurons in driving seizures, and their role was evaluated insilico using transcriptomic changes induced by valproic-acid, which showed opposing effects in the two cell-types. Additionally, we revealed novel epileptic and antiepileptic mechanisms and predicted drugs using causal inference, outperforming the present drug repurposing approaches. These well-powered findings not only expand the understanding of TLE and seizure oscillation, but also provide predictive biomarkers of epilepsy, cellular and causal micro-circuitry changes associated with it, and a drug-discovery method focusing on these events.

Psoriasis is a chronic, inflammatory skin disease, frequently associated with dyslipidemia. Lipid disturbance in psoriasis affects both circulatory system and cutaneous tissue. Epidermal Langerhans cells (LCs) are tissue-resident DCs that maintain skin immune surveillance and mediate various cutaneous disorders, including psoriasis. However, the role of LCs in psoriasis development and their lipid metabolic alternation remains unclear. Here, we demonstrate that epidermal LCs of psoriasis patients enlarge with longer dendrites and possess elevated IL-23p19 mRNA and a higher level of neutral lipids when compared with normal LCs of healthy individuals. Accordantly, epidermal LCs from imiquimod-induced psoriasis-like dermatitis in mice display overmaturation, enhanced phagocytosis, and excessive secretion of IL-23. Remarkably, these altered immune properties in lesional LCs are tightly correlated with elevated neutral lipid levels. Moreover, the increased lipid content of psoriatic LCs might result from impaired autophagy of lipids. Bulk RNA-Seq analysis identifies dysregulated genes involved in lipid metabolism, autophagy, and immunofunctions in murine LCs. Overall, our data suggest that dysregulated lipid metabolism influences LC immunofunction, which contributes to the development of psoriasis, and therapeutic manipulation of this metabolic process might provide an effective measurement for psoriasis.

Invariant natural killer T cell (iNKT) subsets are differentially distributed in various immune organs. However, it remains unclear whether iNKT cells exhibit phenotypical and functional differences in different peripheral organs and how thymic iNKT cells emigrate to peripheral organs. Here, we used single-cell RNA-seq to map iNKT cells from peripheral organs. iNKT1 cells from liver, spleen, and lymph node appear to have distinct phenotypic profiles and functional capabilities. However, iNKT17 transcriptomes were comparable across peripheral organs. In addition, by integrating data with a thymic iNKT cell study, we uncovered a transient population of recent thymic emigrants, a cluster of peripheral iNKT cells with high expression of transcription factor Kruppel-like factor 2 (Klf2). Deletion of Klf2 led to a severe impairment of iNKT differentiation and migration. Our study revealed that iNKT subsets are uniquely distributed in peripheral organs with some inter-local tissue variation, especially for iNKT1 cell, and identified Klf2 as a rheostat for iNKT cell migration and differentiation.

Astrocytes have many important functions in the brain, but their roles in psychiatric disorders and their responses to psychotropic medications are still being elucidated. Here, we used gene enrichment analysis to assess the relationships between different astrocyte subtypes, psychiatric diseases, and psychotropic medications (antipsychotics, antidepressants and mood stabilizers). We also carried out qPCR analyses and "look-up" studies to assess the chronic effects of these drugs on astrocyte marker gene expression. Our bioinformatic analysis identified gene enrichment of different astrocyte subtypes in psychiatric disorders. The highest level of enrichment was found in schizophrenia, supporting a role for astrocytes in this disorder. We also found differential enrichment of astrocyte subtypes associated with specific biological processes, highlighting the complex responses of astrocytes under pathological conditions. Enrichment of protein phosphorylation in astrocytes and disease was confirmed by biochemical analysis. Analysis of LINCS chemical perturbagen gene signatures also found that kinase inhibitors were highly discordant with astrocyte-SCZ associated gene signatures. However, we found that common gene enrichment of different psychotropic medications and astrocyte subtypes was limited. These results were confirmed by "look-up" studies and qPCR analysis, which also reported little effect of psychotropic medications on common astrocyte marker gene expression, suggesting that astrocytes are not a primary target of these medications. Conversely, antipsychotic medication does affect astrocyte gene marker expression in postmortem schizophrenia brain tissue, supporting specific astrocyte responses in different pathological conditions. Overall, this study provides a unique view of astrocyte subtypes and the effect of medications on astrocytes in disease, which will contribute to our understanding of their role in psychiatric disorders and offers insights into targeting astrocytes therapeutically.

The tuberous root of Tetrastigma hemsleyanum Diels et Gilg (T. hemsleyanum) is a traditional Chinese medicine with a wide range of clinical applications. However, the scarcity of its wild resources, its low yield, and the variable quality that results from its artificial cultivation leads to expensive market prices that are not conducive to the further industrial development of T. hemsleyanum. In this study, transcriptomic and non-targeted metabolomic analyses were integrated to explore the underlying molecular mechanisms and metabolite biosynthesis that occur during its root development. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that differentially expressed genes (DEGs) were predominantly enriched for processes associated with flavonoid and phenylpropanoid biosynthesis, starch and sucrose metabolism, and plant hormone signal transduction. Genes related to lignin were downregulated in tuberous roots (TRs), resulting in a decrease in lignification and the downregulation of metabolites related to flavonoids and phenylpropanoid biosynthesis. In addition, the expression levels of starch- and sucrose-related genes were upregulated in TRs. The root development of SYQ is also related to IAA, GA, ABA, and JA signaling pathways. Collectively, this study lays the foundation for analyzing the root development and quality-modulating mechanisms employed by T. hemsleyanum; this will be beneficial in conducting molecular-assisted breeding and controlling its secondary metabolite production.

Single-cell genomic technologies offer vast new resources with which to study cells, but their potential to inform parameter inference of cell dynamics has yet to be fully realized. Here we develop methods for Bayesian parameter inference with data that jointly measure gene expression and Ca2+ dynamics in single cells. We propose to share information between cells via transfer learning: for a sequence of cells, the posterior distribution of one cell is used to inform the prior distribution of the next. In application to intracellular Ca2+ signalling dynamics, we fit the parameters of a dynamical model for thousands of cells with variable single-cell responses. We show that transfer learning accelerates inference with sequences of cells regardless of how the cells are ordered. However, only by ordering cells based on their transcriptional similarity can we distinguish Ca2+ dynamic profiles and associated marker genes from the posterior distributions. Inference results reveal complex and competing sources of cell heterogeneity: parameter covariation can diverge between the intracellular and intercellular contexts. Overall, we discuss the extent to which single-cell parameter inference informed by transcriptional similarity can quantify relationships between gene expression states and signalling dynamics in single cells.

Corneal keratoconus (KC) is a dilated (ectatic) corneal disease characterized by a central thinning of the cornea, which causes protrusion into a conical shape that seriously affects vision. However, due to the complex etiology of keratoconus, its entire mechanism remains unclear and there is no mechanism-directed treatment method. Ferroptosis is a novel programmed cell death mechanism related to lipid peroxidation, stress, and amino acid metabolism, which plays a crucial role in various diseases. This study aimed to explore the relationship between keratoconus and ferroptosis, to provide new insights into the mechanism of keratoconus development, and potential treatment options based on further elucidation of this mechanism. The corresponding mRNA microarray expression matrix data of KC patients were obtained from GEO database (GSE204791). Weighted co-expression network analysis (WGCNA) and support vector machine recursive feature elimination (SVM-RFE) were selected to screen hub genes, which were overlapped with ferroptosis genes (FRGs) from FerrDb. GO and GSEA were performed to analyze differential pathways, ssGSEA was used to determine immune status, and then, feasible drugs were predicted by gene-drug network. Additionally, we predicted the miRNA and IncRNA of hub genes to identify the underlying mechanism of disease so as to predict treatment for the disease. The epithelial transcriptome from keratoconus tissue mRNA microarray data (GSE204791) was extracted for the main analysis, including eight epithelial cells and eight epithelial control cells. The differential genes that were overlapped by WGCAN, SVM-RFE and FRGs were mainly related to oxidative stress, immune regulation, cellular inflammation, and metal ion transport. Through further analysis, aldo-keto reductase family 1 member C3 (AKR1C3) was selected, and negatively correlated with mature CD56 natural killer (NK) cells and macrophages. Then, gene-drug interaction network analysis and miRNA prediction were performed through the website. It was concluded that four immune-related drugs (INDOMETHACIN, DAUNORUBICIN, DOXORUBICIN, DOCETAXEL) and a miRNA (has-miR-184) were screened to predict potential drugs and targets for disease treatment. To our knowledge, this was the first report of KC being associated with ferroptosis and prompted search for differential genes to predict drug targets of gene immunotherapy. Our findings provided insight and a solid basis for the analysis and treatment of KC.