Daijiworld Media Network – New Delhi

New Delhi, Feb 22: A potential breakthrough in the treatment of type 1 mediated chronic inflammatory skin diseases (ISD) has emerged, as researchers have identified receptor-interacting serine/threonine-protein kinase 1 (RIPK1) inhibition as a promising therapeutic target. The findings suggest that blocking RIPK1 may prevent keratinocyte cell death and significantly reduce skin inflammation in preclinical models of lichen planus (LP) and cutaneous lupus erythematosus (CLE).

Lichen planus and cutaneous lupus erythematosus are debilitating inflammatory skin disorders that affect the skin, hair, nails, and mucous membranes, often leading to considerable discomfort and reduced quality of life. Both conditions are driven by type 1 immune responses and are marked by excessive keratinocyte cell death, including apoptosis and necroptosis. RIPK1 plays a central role in regulating programmed cell death and inflammatory pathways, making it an attractive focus for therapeutic intervention.

In the study, researchers conducted RNA sequencing on 179 ISD samples. The analysis revealed that markers associated with apoptosis, such as caspase 8, and necroptosis markers including RIPK3 and MLKL, were significantly elevated in lesions of LP and CLE patients. These results reinforced the theory that abnormal regulation of cell death contributes directly to disease progression.

The research team then evaluated eclitasertib, a novel RIPK1 inhibitor, across multiple experimental systems. In a murine model of tumour necrosis factor-alpha (TNF-α)-induced systemic inflammatory response syndrome, oral administration of eclitasertib shortly after TNF-α exposure restored body temperature, indicating protection against systemic inflammation.

Further experiments using reconstructed human epidermis stimulated with T cell supernatants derived from LP and CLE demonstrated that RIPK1 inhibition effectively prevented keratinocyte cell death. It also restored normal epidermal structure and significantly reduced the release of pro-inflammatory cytokines, including IL-1α, IL-1β, TNF-α, and CCL20.

Additionally, ex vivo cultures of skin biopsy samples from LP and CLE patients treated with eclitasertib showed downregulation of disease-specific genes and inflammatory signalling pathways, further supporting its therapeutic potential.

The findings indicate that RIPK1 inhibition may simultaneously address two key pathological mechanisms in type 1 mediated chronic inflammatory skin diseases — excessive epidermal cell death and immune-driven inflammation.

However, researchers caution that the results are currently limited to preclinical models, including animal systems, reconstructed human tissue, and laboratory cultures. Clinical trials will be essential to assess safety, tolerability, and effectiveness in patients.

If future human studies confirm these results, RIPK1 inhibition could offer a novel and targeted strategy for managing chronic inflammatory skin conditions by tackling both cell death and inflammation at their source.