Biological sex is a key modifier of HIV pathogenesis, with women more frequently achieving spontaneous viral control than men. Toll-like receptor 7 (TLR7), an endosomal RNA sensor encoded on the X chromosome that escapes X-inactivation, plays a pivotal role in antiviral immunity and is increasingly targeted in HIV cure strategies aimed at reversing viral latency. However, it remains unclear whether TLR7-driven immune responses differ by sex in the context of HIV infection.

Psoriasis is a common chronic immune-mediated inflammatory skin disease that presents significant challenges in clinical management. Gentiopicroside (GPS), a bioactive compound derived from Gentiana scabra, has been reported to possess anti-inflammatory and immunomodulatory properties. However, its potential role in the treatment of psoriasis remains unclear. This study aimed to investigate the therapeutic effects of GPS on psoriasis-like dermatitis and elucidate its underlying mechanisms. A psoriasis-like dermatitis model was established in BALB/c mice using imiquimod (IMQ). The therapeutic efficacy of GPS was evaluated based on clinical and histopathological improvements. Flow cytometry was used to analyze immune cell populations in the spleen and peripheral blood. In vitro, the effects of GPS on bone marrow-derived dendritic cells (BMDCs) were assessed in an inflammatory model. RNA sequencing was performed to identify differentially expressed genes and key signaling pathways in BMDCs after GPS treatment. Molecular docking was employed to predict the binding affinity between GPS and potential targets, which were further validated using Western blotting and immunofluorescence. GPS treatment significantly alleviated psoriasis-like skin lesions in IMQ-induced mice, improving both clinical manifestations and histopathological alterations. GPS reduced the proportions of lymphocytes and dendritic cells and attenuated Th17-driven inflammation, thereby contributing to a more balanced immune milieu. In vitro, GPS inhibited the maturation and activation of BMDCs. Transcriptomic profiling demonstrated that GPS modulated multiple immune- and cytokine-associated pathways, particularly the NF-κB signaling pathway. Molecular docking suggested a strong binding affinity between GPS and NF-κB p65, while Western blotting and immunofluorescence confirmed that GPS suppressed phosphorylated NF-κB p65 nuclear translocation. GPS exerts anti-psoriatic effects through multimodal mechanisms, including immunomodulation and suppression of NF-κB activation. These findings provide experimental evidence and a theoretical basis for the development of GPS as a potential therapeutic agent for psoriasis.

Psoriasis is an autoimmune skin disease whose precise pathogenesis remains incompletely understood. This study uncovered a critical role of lactate-induced metabolic reprogramming via GPR81 in the development of imiquimod-induced murine psoriasis. The activation of the lactate receptor GPR81 was found to be essential for reducing prostaglandin E2 (PGE2), a known lipid marker associated inflammation. GPR81 knockout (GPR81[-]/[-]) mice exhibited elevated PGE2 levels in epidermis, further supporting PGE2 as a metabolic indicator of psoriasis and suggesting its role in disease exacerbation. Similarly, treatment with reserpine, a newly identified GPR81 inhibitor, led to increased PGE2 levels compared to the control group. Mechanistically, inhibition of GPR81 upregulated cyclooxygenase-2 (COX-2), a rate-limiting enzyme in PGE2 synthesis. Moreover, GPR81[-]/[-] mice displayed enhanced immune cell activation and proliferation relative to wild-type (WT) mice, including a marked increase in M1-polarized macrophages, elevated CD8[+] and CD4[+] T cell populations, and heightened secretion of pro-inflammatory cytokines such as IL-17, IL-23, and TNF-α. These alterations were associated with aggravated dermatological manifestations, including pronounced scaling, epidermal hyperplasia, and inflammatory cell infiltration accompanied by elevated cytokine production. Conversely, administration of the GPR81 agonist 3,5-Dihydroxybenzoic Acid (3,5-DHBA) significantly suppressed COX-2 expression and PGE2 levels by inhibiting PKA activation, thereby alleviating psoriatic symptoms. Collectively, these findings reveal a novel mechanism whereby GPR81 reprograms PGE2 synthesis through PKA-mediated downregulation of COX-2, highlighting GPR81 as a promising therapeutic target. The use of 3,5-DHBA demonstrates significant therapeutic potential for the treatment of autoimmune disease.

Psoriasis is a chronic immune-mediated skin disorder characterised by abnormal keratinocyte proliferation and cutaneous inflammation. ACTR3 (actin-associated protein 3) is significantly overexpressed in both cutaneous malignant tumours and psoriatic keratinocytes, and is recognised as a potential key nodal molecule linking tumours to inflammatory skin conditions. Lysine 2-hydroxyisobutyrylation (Khib)-a critical post-translational modification-exerts regulatory effects on the pathogenesis of various diseases; however, its specific role in psoriasis pathogenesis remains elusive. In this study, we demonstrated that elevated ACTR3 expression in cutaneous tumours and psoriasis promotes abnormal keratinocyte proliferation in psoriasis. Khib-modified protein profiles in epidermal tissues from psoriatic patients and healthy controls were analysed, leading to the identification of ACTR3 as a differential target protein. Results showed that Khib modification levels at the K42 site of ACTR3 were significantly reduced in lesional tissues from psoriatic patients and imiquimod (IMQ)-induced psoriatic mice. Further validation using ACTR3 K42A mutation experiments confirmed that decreased Khib modification at this site exacerbates IMQ-induced psoriatic inflammation and keratinocyte proliferation. Deacetylases Sirt1 and HDAC1 were found to reduce ACTR3 Khib modification levels, thereby regulating ACTR3 expression and subsequent keratinocyte (KC) proliferation. Additionally, signalling pathway analysis revealed that downregulated K42-Khib modification of ACTR3 enhances keratinocyte proliferation by activating the TAK1-MK2-HSP27 pathway. Notably, TAK1 antagonists effectively reversed abnormal keratinocyte proliferation and psoriatic inflammation induced by the ACTR3 K42A mutation. This study elucidates that reduced Khib modification at the ACTR3 K42 locus promotes keratinocyte proliferation via regulation of the TAK1-MK2-HSP27 signalling pathway, offering a previously undescribed molecular insight into psoriasis pathogenesis.

Formula PSORI-CM01 has been used to alleviate psoriasis symptoms. Here, we developed a novel formula, Touxie Quyin Compound (TQC), which is composed of PSORI-CM01 and Artemisia annua. This study evaluated its therapeutic effects and the underlying mechanisms mediated by histone lactylation in psoriasis recurrence. Imiquimod (IMQ) was applied to induce psoriasis-like lesions in mice, with vaseline, PSORI-CM01, and TQC treatments used for comparison. After a 7-day IMQ treatment and 30-day drug-free interval, mice were re-challenged to induce psoriasis relapse and subsequently treated with PSORI-CM01 and TQC. PSORI-CM01 and TQC markedly alleviated psoriatic symptoms and reduced H3K18 lactylation in the IMQ group, with TQC showing greater inhibiting effect. ChIP-seq data revealed that genes with hypomodified H3K18la peaks in the IMQ + TQC group compared to the IMQ group were related to lipid metabolism, and transcriptomic analysis also indicated TQC-downregulated genes were associated with lipid metabolism. Correspondingly, TQC reduced the H3K18 lactylation and expression of lipid uptake-related genes Fabp4/5 in psoriatic skin lesions of mice. In addition, the infiltration levels of CD8+CD103+ tissue-resident memory T (TRM) cells in IMQ mice, as well as the expression of Fabp4/5 within CD3+ T cells, could also be reduced by TQC. Lactate treatment reversed the inhibitory effect of TQC on CD8+CD103+ TRM cells. Collectively, TQC may alleviate psoriasis recurrence by suppressing histone lactylation-mediated Fabp4/5 and CD8⁺CD103⁺ TRM cell infiltration, highlighting its potential as a therapeutic strategy for preventing disease relapse.

Background: The combination of photodynamic therapy (PDT) and immunotherapy has been explored as an innovative approach to enhance efficacy against tumors. However, PDT shows limited effectiveness in treating deep-seated tumors, as light and lasers do not sufficiently penetrate tissue. Methods: Herein, we introduced a nanocarrier (NPVR) via self-assembly, using an amphiphilic copolymer to co-deliver the hydrophobic photosensitizer verteporfin (VP) and the immunoadjuvant imiquimod (R837). Results: Our X-ray-induced photodynamic therapy (X-PDT) mechanism induced NPVR to generate a large amount of cytotoxic reactive oxygen species (ROS), which directly killed cancer cells. Moreover, the released R837 facilitated immunogenic cell death following the X-PDT process and promoted the maturation of dendritic cells (DCs), thereby eliciting immune responses against malignant triple-negative breast cancer (TNBC). In animal experiments, the combined therapy using NPVR showed a tumor growth inhibition rate of ~70%. Conclusions: This novel strategy opens new avenues to designing next-generation nanomedicines for use in immunotherapy and other combination therapies.

Background: Psoriasis frequently relapses after treatment withdrawal, consistent with persistent epigenetic programs in lesional immune cells. Lysine acetylation is a reversible regulatory layer linking chromatin accessibility, transcription factor activity, and immune-cell effector programs; yet, its cell-type-resolved landscape and clinical stratification value in psoriasis remain incompletely defined. Methods: We integrated four bulk transcriptome cohorts of psoriatic and healthy skin (746 psoriasis, 515 controls) with two public skin scRNA-seq datasets. A diagnostic acetylation-regulator signature was derived from 33 curated acetylation regulators, and acetylation endotypes were defined by unsupervised clustering. The cell-type-specific expression was mapped at the single-cell resolution. Key regulators were validated by quantitative real-time polymerase chain reaction (qRT-PCR) in an imiquimod-induced psoriasis-like mouse model, and further verified in an independent dataset (GSE136757). Motif enrichment and drug-target mining were used to prioritize transcriptional regulators and candidate epigenetic therapeutics. Results: Sixteen acetylation regulators were differentially expressed in bulk skin, with histone deacetylase (HDAC1) showing the strongest upregulation and lysine acetyltransferase (KAT2A) the strongest downregulation. A 13-gene acetylation signature discriminated psoriasis from controls (area under the curve, AUC 0.886) and separated lesional samples into two acetylation endotypes with divergent pathway states (hypoxia-glycolysis versus oxidative-stress-dominated programs). Single-cell mapping demonstrated immune-restricted acetylation modules, including CREB binding protein (CREBBP)-enriched neutrophils, histone deacetylase 1 (HDAC1)-high cluster of differentiation (CD)8[+] T cells, and lysine acetyltransferase 6A (KAT6A)/lymphoid enhancer binding factor (LEF1)-enriched CD4[+] and regulatory T cell (Treg) subsets, coincident with interleukin (IL)-17-related inflammatory programs. In mice, qRT-PCR confirmed the coordinated dysregulation of hub genes and highlighted Hnf1a and Kat6a as reproducible candidates. External validation using the GSE136757 dataset further supports their robust diagnostic performance. Motif analysis nominated interferon regulatory factor (IRF4), YY transcription factor (YY2), and zinc finger protein (ZNF404) as putative transcriptional mediators downstream of acetylation programs, and drug-target mining prioritized epigenetic compounds with subtype-relevant potential, including histone deacetylase (HDAC) inhibitors (e.g., entinostat) and the p300/CREB binding protein (CBP) inhibitor A485. Conclusions: This integrative atlas links acetylation regulators to specific immune compartments, defines acetylation endotypes associated with distinct inflammatory programs, and provides a rationale for stratified epigenetic target selection in psoriasis.

Psoriasis is characterized by abnormal keratinocyte proliferation and BIRC5, also known as survivin, plays a critical role in the pathogenesis of psoriasis. However, the regulatory role of BIRC5 in psoriasis progression remains unclear. To elucidate the mechanisms by which BIRC5 regulates psoriasis, we used a mouse model of imiquimod (IMQ)-induced psoriasis characterized by psoriasis area and severity index (PASI) scores and epidermal hyperplasia. Immunohistochemistry and western blotting were performed to assess cell proliferation, autophagy, and apoptosis in vivo. The M5 (Oncostatin-M, IL-22, TNF-α, IL-1α, and IL-17 A) was used to treat HaCaT cells for the psoriatic cell model. M5-triggered HaCaT cells were used to investigate the function of BIRC5 in cell proliferation, apoptosis, and autophagy in vitro. The deletion of BIRC5 alleviated IMQ-induced psoriasis-like skin lesions, reduced the PASI scores, and decreased epidermal thickness. Inhibition of BIRC5 suppressed proliferation, facilitated apoptosis, and activated autophagy in these IMQ-induced mice. Consistent with the animal experiment results, M5 accelerated the proliferation of HaCaT cells, whereas inhibited the apoptosis and autophagy of HaCaT cells; however, BIRC5 knockdown partially reversed these effects. Additionally, silencing BIRC5 inhibited the phosphorylation of PI3K, AKT, and mTOR. Furthermore, 3-MA or SC79 treatment negated the autophagy- and apoptosis-enhancing effect of BIRC5 inhibition, as well as the inhibitory effect on HaCaT cell proliferation. Collectively, BIRC5 may accelerate keratinocyte proliferation and inhibit keratinocyte apoptosis through PI3K/AKT/mTOR-mediated autophagy.