Targeted protein degradation (TPD) technologies provide huge opportunities for drug discovery, but degrading transmembrane (TM) targets remains challenging. Since TM proteins are canonically folded on the endoplasmic reticulum (ER) membrane, we hypothesized that harnessing ER-associated degradation (ERAD) may enable efficient degradation of TM proteins. Here, we established a TPD technology hijacking ERAD and named it ERAD-engaging chimeras (ERADECs), capable of degrading TM targets with high efficacy. We identified desonide as a binder of SYVN1, an ER E3 ligase mediating ERAD. We designed ERADECs targeting programmed death-ligand 1 (PD-L1) by connecting desonide to a known PD-L1 ligand and observed SYVN1- and ERAD-dependent PD-L1 degradation with high efficacy. Functionally, these ERADECs exhibited stronger tumor suppression and PD-L1-lowering effects than a clinically used PD-L1 antibody in vivo. The concept of ERADECs is also expandable to other membrane targets. Collectively, we established a platform technology hijacking ERAD to selectively degrade TM targets with remarkable efficiency.

Inhibiting telomerase could lead to telomere shortening, chromosomal instability, and eventually cell death in cancer cells. The use of steroids in cancer treatment is significant; besides, drug repurposing can be a quicker and less expensive method of drug discovery than de novo drug development. Accordingly, diverse 280 steroidal drugs-following a pharmacophore-based rationale-were docked against telomerase receptor and compared to the co-crystallized inhibitor (BIBR1532) as a reference standard. Additionally, a molecular dynamics simulation for 200 ns was performed to confirm the docking results. Moreover, the six steroidal drugs (Betamethasone disproportionate, Beclomethasone disproportionate, Clobetasone butyrate, Desonide, diflucortolone valerate, and Hydrocortisone butyrate) were selected for further in vitro investigation. The antitumor activities of the six steroidal drugs against H1299, HuH7, HCT116, A549, MDA-MB-231, MCF7, PC3, MG63, and A375 cancer cell lines, besides OEC and HSF normal cell lines, were evaluated and compared to doxorubicin (Dox) as a reference positive standard. Especially, Clobetasone butyrate represented the better cytotoxicity against seven cancer cell lines (H1299, HuH7, HCT116, MDA-MB-231, PC3, MG63, and A375) with IC50 values of 12.56, 13.95, 12.00, 17.51, 11.69, 20.64, and 20.21 µg/mL, respectively. The outstanding antitumor six steroidal drugs were further investigated for their telomerase downregulatory potentials. All analogs recorded outstanding downregulatory results against telomerase, especially Clobetasone butyrate, Desonide, Diflucortolone valerate, and Hydrocortisone butyrate, where the protein expression for telomerase was downregulated up to 0.66-, 0.76-, 0.56-, and 0.73-fold change for clobetasone butyrate, desonide, diflucortolone valerate, and hydrocortisone butyrate, respectively, compared to the control.

Atopic dermatitis (AD), the most common chronic inflammatory skin disease, is characterized by intense pruritus and varying degrees of cutaneous inflammation. Current therapeutic modalities (such as topical corticosteroids and biologics) can control symptoms in the short term, but limitations including extremely low bioavailability and significant side effects substantially restrict their clinical efficacy in AD management. Therefore, more precise and safer local management strategies for AD represent the most promising direction for future development. As a biomaterial with a three-dimensional network structure combining biomimetic properties and sustained drug delivery capability, hydrogel emerges as an optimal carrier choice. Multiple clinical trials have demonstrated that Desonide hydrogel provides substantial benefits to patients, making the design of multifunctional hydrogel dressings a research hotspot in recent years. This review first summarizes the feasible options for drug loading in hydrogels, then focuses on the advantages and disadvantages of different hydrogel types and drug delivery methods, and finally addresses the challenges and solutions for translating innovative hydrogels into clinical practice. Aimed at integrating perspectives from materials science, dermatology, and translational medicine, this review establishes a theoretical framework for the rational design of innovative hydrogels in local AD therapy.

Background/Objectives: A novel ophthalmic formulation, XanterDES, containing 0.2% xanthan gum and 0.025% desonide sodium phosphate (DES), was developed to alleviate ocular surface discomfort and irritation. This study aimed to evaluate its pharmacodynamic properties and to characterize its rheological behavior and mucoadhesive characteristics, compared to another formulation containing 0.2% hyaluronic acid and 0.001% hydrocortisone (HYD). Methods: A rabbit (New Zealand White) model of LPS-induced uveitis was used to test different concentrations of DES on ocular markers of inflammation. The efficacy of XanterDES and HYD on induced dry eye was evaluated by assessing tear volume and corneal damage in C57BL/6 mice exposed to a controlled environmental chamber. The rheological and mucoadhesive properties of XanterDES and HYD were assessed using a HAAKE RheoStress RS600 rheometer and a TA-XT2 texture analyzer, respectively. Results: In the uveitis model, unlike DES 0.25%, a low concentration of 0.025% DES showed a significant inhibitory activity localized to the eye surface and effectively reduced corneal edema. In the dry eye model, XanterDES demonstrated superior efficacy compared to HYD, effectively preventing both tear volume reduction and corneal damage. XanterDES also demonstrated pseudoplastic and enhanced mucoadhesive properties compared to HYD. Conclusions: The ancillary anti-inflammatory effects of a low dose of DES combined with the biophysical properties of xanthan gum are supportive of a favorable therapeutic profile, promoting the maintenance or restoration of ocular surface homeostasis while minimizing the risk of adverse effects typically associated with standard-dose corticosteroids. The comparison with another low-dose corticosteroid highlights the superiority of XanterDES in pharmacodynamic and biophysical performance.

This study evaluates the efficacy and safety of soothing moisturizing repairing cream combined with desonide in the treatment of atopic dermatitis (AD) in children in the real world. A total of 37 children with AD were randomly divided into experimental (17) and control (20) groups. For the experimental group, treated with moisturizing cream combined with desonide cream, the maintenance period was with moisturizer alone. For the control group, treated solely with desonide, the maintenance period was with nothing. Clinical assessments were made before and 1, 2, and 4 weeks after treatment. Efficacy indicators are compared between the 2 groups, and the relieving effect of moisturizer on the maintenance period of AD in children is observed. Adverse reactions are also recorded. After 4 weeks of treatment, the cure rate and effectiveness rate in the experimental group were 52.9% and 100%, respectively, compared to 0% and 60% in the control group; the estimated median maintenance time was 48 days for the control group and 73 days for the experimental group. The incidence of adverse reactions shows no statistical significance. The combination of moisturizing cream and desonide in the treatment of AD in children is highly effective and safe. It is worth promoting for clinical application due to its significant therapeutic effects and high safety profile.