Targeted siRNA Therapy for Psoriasis: Translating Preclinical Potential into Clinical Treatments

Figures & data

Table 1 Therapeutic Role of siRNA in Psoriasis and Its Potential Applications

Reference	Gene	Pathway	Cell	Potential Applications
[14]	FGFR2		Keratinocytes	This study implicates miR-125b as a potential therapeutic target for psoriasis
[15]	NFAT2		Keratinocytes	NFAT2 is a key regulator of keratinized cell proliferation and a potential molecular target associated with lithium-induced psoriasis
[16]	TRAF3IP2		Keratinocytes/endothelial cells	TRAF3IP2 may be a potential therapeutic target for psoriasis
[17]	G1P3		Keratinocytes	Expression of G1P3 protein contributes to the maintenance of hyperproliferation of keratinized cells during psoriasis development and is a potential target for the treatment of psoriasis
[18]	AKR1B10		Keratinocytes	Demonstrated to induce hyperproliferation of keratinized cells by knockdown validation assays, providing a target for further therapeutic options in psoriasis
[20]	circIGF1R	miR-194-5p/CDK1	Keratinocytes	circIGF1R may serve as a potential therapeutic target for psoriasis
[21]	PTTG2		Keratinocytes	PTTG2 might be a potential therapeutic target for psoriasis through inducing epithelial-to-mesenchymal transition (EMT) via regulating the expression of vimentin and E-cadherin.
[22]	MIR31HG	NF-κB	Keratinocytes	MIR31HG plays an important role in the regulation of keratinocyte hyperproliferation in psoriasis and may be an attractive therapeutic target
[23]	KPNA2		Keratinocytes	Clarifying the function of KPNA2 in cell proliferation will be a focal point for the development of novel therapies targeting KPNA2.
[24]	WT1		Keratinocytes	Providing a new target for psoriasis treatment
[25]	WTAP		Keratinocytes	Overexpression of WTAP may contribute to the pathogenesis of psoriasis by regulating cell cycle progression, WTAP is a potential therapeutic target for psoriasis treatment.
[27]	EGR1/PLK2		Keratinocytes	The results provide a basis for the development of new compounds for the treatment of proliferative skin diseases such as psoriasis
[28]	KRT16	ERK	Keratinocytes	Silencing KRT16 inhibits keratinocyte proliferation and VEGF secretion in psoriasis via inhibition of ERK signaling pathway, which provides a basic theory in the treatment of psoriasis.
[29,55]	K17		Keratinocytes	Anti-K17 therapy is an effective treatment option for psoriasis, and the K17 molecule, as a new target, may hold tremendous potential for the treatment of psoriasis in the future.
[32]	ENO1/K17		Keratinocytes	Revealed the mechanism by which K17 interacts with ENO1 to promote glycolysis and proliferation of KCs, provides a new perspective for the study of the correlation between proliferation and metabolism.
[35,36]	STAT1/STAT3	JAK/STAT	Keratinocytes	Silencing STAT1 and STAT3 can inhibit the proliferation of keratinocytes.
[37]	CK2	STAT3/AKT	Keratinocytes	CK2 may be a target for the treatment of psoriasis
[38]	BCL2L1/IGF-1R		Keratinocytes	BCL2L1 and IGF-1R are important targets for the inhibition of keratinocyte hyperproliferation by siRNA technology
[40]	GRHL2		Keratinocytes	Promotion of keratinocyte differentiation by miR-217 is partially mediated by the inhibition of its direct target GRHL2. And may represent a novel therapeutic target for psoriasis treatment.
[41,42]	S1P		Keratinocytes	S1P lyase is a modulating factor for proliferation and differentiation, and support its potential as a therapeutic target for psoriasis in human keratinocytes.
[43]	Cathepsin B		Keratinocytes	Cathepsin B might be a promising therapeutic target for psoriasis-like lesion, which helps to develop an anti-psoriatic agent
[44]	Gasdermin D		Keratinocytes	Targeted focal death could be considered a therapeutic strategy for psoriasis
[48]	AQP1		Endothelial cells	The present study confirms that AQP1 is a pro-angiogenic protein and therefore may be a candidate target for anti-angiogenic molecules
[49]	HIF-1α		Keratinocytes	May provide insights into the pathophysiology of neuro inflammatory skin diseases such as psoriasis
[50]	EDIL3	αvβ3- FAK/MEK/ERK	Endothelial cells	EDIL3 and αvβ3- FAK/MEK/ERK signaling pathways will provide valuable therapeutic targets for controlling angiogenesis
[53]	TSG-6		Neutrophils	Blocking neutrophil recruitment by MSCs-IT or TSG-6 has potential for therapeutic application in human psoriasis.
[54,69]	USP15		Keratinocytes	USP15 may be a potential target for the treatment of psoriasis
[56–58]	NFKBIZ	MAPK/NF-κB	Keratinocytes	Future studies elucidating the regulation of IκBζ will enhance its potential as a therapeutic target in psoriasis and other inflammatory diseases
[60]	REL		T-Cells	Susceptibility gene Rel could be targeted to treat and prevent psoriasis
[61]	PLA2G4B		Keratinocytes	Phospholipase inhibition-based therapy reveals potential for anti-psoriasis drugs
[62]	HSP90/60	MAPK	Keratinocytes	OMT-mediated reduction of HSP90 and HSP60 in keratinocytes of psoriasis mice further confirmed the anti-pruritic effect of OMT.
[63]	IFI27		Keratinocytes	This study demonstrates that IFI27 is required for cell proliferation in vitro and in vivo, and that if27 may be a suitable target for the development of a novel anti-psoriasis therapy
[70]	SERPINB2		Neutrophils	Since SERPINB2 expression is positively correlated with psoriasis severity, it may be used as a biomarker for psoriasis
[71]	Notch-1		Endothelial cells	The Notch-ligand receptor pathway may regulate vascular dysfunction and pro-inflammatory mechanisms involved in the pathogenesis of psoriasis, suggesting that targeted blockade of this pathway may have important therapeutic implications.
[72]	Gasdermin B		Keratinocytes	This study suggests that Gasdermin B may be associated with psoriasis
[73]	βTrCP	NF-κB	Keratinocytes	βTrCP is involved in the NF-κB signaling mediated-, psoriasis-related inflam-mation and represent a novel target for developing agents to treat psoriasis.
[74]	bFGF	JNK/SAPK	Endothelial cells	Modulation of the JNK/SAPK signaling pathway may be a promising therapeutic approach for treating angiogenesis-related diseases
[75]	STC1		Keratinocytes	Targeting STC1 and/or signaling molecules induced by STC1 could be a new therapeutic strategy for controlling diseases involving dysregulation of epidermal and dermal interactions.
[76]	ULK1		Keratinocytes	ULK1 Inhibitors May Be a Potential Option for Treating or Preventing Psoriasis Recurrence
[77]	Tcf7l1		Keratinocytes	Targeting the Tcf7l1–LCN2 axis may be one of the approaches in managing skin diseases with dysregulated keratinocyte differentiation.
[78]	S100A7	PI3K/NF-κB	Keratinocytes/endothelial cells	This study findings raise the possibility that psoriasin could be evaluated as a novel antiangiogenic target in psoriasis
[79]	AKT	PI3K/AKT	Keratinocytes	Survivin and the PI3K/AKT signaling pathway could be potential new targets for psoriasis therapy and may provide new ideas for psoriasis treatment
[80]	TREM-1	PI3K	Keratinocytes	This study provides important clues for understanding the potential pathogenesis mechanism of psoriasis in which HIF-1α is regulated by the TREM-1 signaling pathway

Abbreviations: FGFR2, Fibroblast Growth Factor Receptor 2; NFAT2, Nuclear Factor of Activated T Cells 2; TRAF3IP2, TRAF3 Interacting Protein 2; G1P3, Interferon Alpha Inducible Protein 6; AKR1B10, Aldo-Keto Reductase Family 1 Member B10; POMP, Proteasome Maturation Protein; circIGF1R, Circ-Insulin Like Growth Factor 1 Receptor; CDK1, Cyclin Dependent Kinase 1; PTTG2, Pituitary Tumor-Transforming 2; MIR31HG, MIR31 Host Gene; KPNA, Karyopherin Subunit Alpha; WTAP, WT1 Associated Protein; WT1, WT1 Transcription Factor; EGR1, Early Growth Response 1; PLK2, Polo Like Kinase 2; KRT16, Keratin 16; KRT17, Keratin 17; KRT6, Keratin 6; E-FABP, Fatty Acid Binding Protein 5; ENO1, Enolase 1; JAK- STAT, The Janus kinase/Signal Transducer And Activator of Transcription; STAT3, Signal Transducer And Activator of Transcription 3; STAT1, Signal Transducer And Activator of Transcription 1; CK2, Casein Kinase 2; AKT, Threonine Kinase; GRHL2, Grainyhead Like Transcription Factor 2; SGPL1, Sphingosine-1-Phosphate Lyase 1; AQP1, Aquaporin 1; VEGF, Vascular Endothelial Growth Factor; EDIL3, EGF Like Repeats And Discoidin Domains 3; NGF, Nerve Growth Factor; PI3K, Phosphatidylinositol-4,5-Bisphosphate 3-Kinase; MTOR, Mechanistic Target of Rapamycin Kinase; HIF-1α, Hypoxia Inducible Factor 1 Subunit Alpha; TRAF3IP2, TRAF3 Interacting Protein 2; ERK, Extracellular Signal-Related Kinase; TSG-6, TNF Alpha Induced Protein 6; USP15, Ubiquitin Specific Peptidase 15; NFKBIZ, NFKB Inhibitor Zeta; NF-κB, Nuclear Factor Kappa B; PLA2G4B, Phospholipase A2 Group IVB; MAPK, Mitogen-Activated Protein Kinase; HSP90, Heat Shock Protein 90; HSP60, Heat Shock Protein 60; IFI27, Interferon Alpha Inducible Protein 27; PCNA, Proliferating Cell Nuclear Antigen; SAA, Serum Amyloid A; CTSB, cathepsin B; SRF, Serum Response Factor; PC1, polycystin 1; PGRN, Granulin Precursor.

Figure 1 Therapeutic applications of siRNA in targeting pathogenic pathways underlying psoriasis. Therapeutic application of small interfering RNA (siRNA) targets the pathogenic pathways of psoriasis. In a physiological state, skin keratinocytes proliferate normally and fulfill a barrier function. In the pathological state of psoriasis, immune cells activate keratinocytes, leading to their rapid proliferation, abnormal differentiation, and inhibited apoptosis; this also promotes angiogenesis and increases inflammatory cell infiltration. Such activation disrupts the skin barrier function and causes a dysregulation in the normal proliferative capacity of keratinocytes, exacerbating the condition. siRNA therapy represents a promising strategy for treating psoriasis by silencing disease-causing genes. siRNA targets keratinocytes, silencing genes such as Casein Kinase 2 (CK2), WT1 Associated Protein (WTAP), WT1 Transcription Factor (WT1), and Enolase 1 (ENO1), which inhibits their proliferation. This action induces their normal differentiation and promotes apoptosis. Additionally, silencing genes such as Aquaporin 1 (AQP1), Nerve Growth Factor (NGF), and Keratin 16 (KRT16) inhibits Vascular Endothelial Growth Factor (VEGF), thereby hindering angiogenesis in psoriasis; Furthermore, targeting genes such as Ubiquitin Specific Peptidase 15 (USP15) and Keratin 17 (KRT17) can reduce inflammatory cell infiltration and attenuate the inflammatory response.

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