The team of Professor Wang Honglin of the Clinical Research Institute of the First Affiliated Hospital published original scientific research results on new targets for psoriasis treatment

"Easy to relapse after stopping the drug" is an important scientific question
that remains unanswered in the clinical treatment of psoriasis.
It is of great significance to further explore the pathogenesis of psoriasis, screen safe and effective new therapeutic targets and new drug candidate molecules that prolong recurrence time, and natural small molecule compounds containing biological activity are one of
the important tools to find drug targets 。 On December 20, Professor Wang Honglin's team from the Clinical Research Institute of the First People's Hospital Affiliated to Shanghai Jiao Tong University published a report entitled "Targeting the transcription factor HES1 by L-menthol restores protein phosphatase 6 in keratinocytes in models of" in Nature Communications psoriasis", with Zhikai Wang as the first author
.
The study found that the natural small molecule compound L-menthol can target the transcription factor HES1 in keratinocytes, restore protein levels of protein phosphatase 6 (PP6), and have a certain therapeutic effect on psoriasis skin inflammation, which is expected to provide potential therapeutic targets for psoriasis
.

In previous studies, the authors found that the expression level of PP6 was significantly reduced in psoriasis keratinocytes, and the loss of PP6 caused skin inflammation of spontaneous psoriasis in mice, indicating that PP6 plays an important role in psoriasis, suggesting that the restoration of keratinocytes PP6 may become an effective means
for the treatment of psoriasis.
Through phenotypic screening, the authors found that L-menthol was able to upregulate the protein level of PP6 in keratinocytes in inflammatory environments and had a significant therapeutic effect
on imiquimod (IMQ)-induced animal models of psoriasis.

To explore the mechanism of L-menthol upregulation of PP6, the authors used the Target Stability Technique for Drug Affinity Response (DARTS) and found that HES1 was a direct target of L-menthol
.
HES1 is significantly reduced in the epidermis of psoriasis patients compared to healthy people, while L-menthol stabilizes HES1 protein levels
in keratinocytes by inhibiting proteasome degradation.
In addition, the deletion of HES1 in keratinocytes can aggravate IMQ-induced psoriasis skin inflammation, while overexpression of HES1 has the effect
of inhibiting inflammation.
Mechanistically, HES1 acts as a transcription factor that binds to the promoter region of the downstream gene IGBP1 and promotes the transcription
of IGBP1.
IGBP1 is an interaction protein of PP6, which can reduce the E3 ubiquitin ligase CHIP interacting with PP6 and reduce the ubiquitination level of PP6, which can provide a potential therapeutic target
for psoriasis.

The team of Professor Wang Honglin of the First Affiliated Hospital has been engaged in the research of immunological mechanisms and new therapeutic targets of psoriasis for a long time, and has achieved a large number of original scientific research results
.
These include the discovery that RNA viruses can infect and induce the occurrence and development of psoriasis, the discovery of small molecules of drug candidates that selectively inhibit T17 differentiation, and the successful implementation of targeted sensory nerve therapy for psoriasis
.
These achievements have been widely concerned and highly praised by experts and scholars at home and abroad, and 65 academic papers have been published in authoritative journals such as Immunity, Science Advances, EMBO Molecular Medicine, Nature Communications, etc.
, and 7 national invention patents and 3 PCT patents have been obtained
。 Since its establishment in 2009, the research team has successively received more than 20 national, provincial and ministerial fund funding
, including the major research and development program of the Ministry of Science and Technology, the National Natural Science Foundation of China Outstanding Youth Fund Project, the National Natural Science Foundation of China Original Exploration Project, and the National Natural Science Foundation of China Key Project.