Deciphering the rules of regulated cell death subroutines by in silico methods

Regulated cell death (RCD) is essential for organismal development, as it plays key roles in organ formation, pathogen defense, and the maintenance of homeostasis. However, while RCD subroutines-such as apoptosis, autophagy, pyroptosis, necroptosis, and ferroptosis-are fundamental for health, their dysregulation can be detrimental, potentially triggering or contributing to a variety of diseases. As a result, the modulation of RCD has emerged as a promising therapeutic strategy for numerous conditions, including infectious, neurodegenerative, autoimmune, cardiovascular diseases, and cancer. Over the past two decades, innovative experimental approaches for modulating RCD have proliferated in medicinal research. In parallel, a growing array of online resources-such as databases, web servers, machine learning (ML)/artificial intelligence (AI) models, omics technologies, and systems biology networks, collectively referred to as "in silico methods"-has become available to accelerate research progress.

Recognizing the potential of these online resources, we have compiled a comprehensive overview of relevant in silico approaches to RCD, aiming to facilitate their effective use in the development of future therapeutic interventions.

RCD-associated databases serve as the foundational data infrastructure for in silico methods, encompassing extensive biological information spanning DNA, RNA, proteins, small molecules, and disease-related data. The continuous curation and expansion of these databases are crucial for elucidating various cell death modalities and visually characterizing the functional dynamics of target molecules across different pathological conditions. Through the integration of AI, ML, multi-omics technologies, and systems biology approaches, we can systematically decode the intricate regulatory networks of RCD and disease progression patterns. This interdisciplinary convergence significantly enhances the discovery pipeline for disease-specific biomarkers and therapeutic targets.