Cell type-specific dissection of cell death programs during ovarian aging.

Abstract

The accurate deconvolution of bulk transcriptomes typically confounds stable physical cell identities with dynamic physiological states, limiting our understanding of complex microenvironmental processes such as ovarian aging. To overcome this, we present DeepMCD, an end-to-end multi-task deep learning framework designed to simultaneously deconvolve cell-type proportions and programmed cell death (PCD) compositional fractions from standard bulk RNA-seq data. By mapping high-dimensional expression profiles into a shared, tokenized latent space, DeepMCD employs a Transformer-based cross-task attention mechanism to explicitly leverage cellular morphological context for calibrating PCD predictions. Concurrently, an adaptive uncertainty-weighting loss ensures balanced optimization, effectively mitigating negative transfer. Extensive benchmarking demonstrates that DeepMCD significantly outperforms state-of-the-art single-task algorithms. Through rigorous ablation and interpretability analyses, we computationally substantiate the biological premise that functional death states are heavily reliant on specific cell-type contexts. Applying DeepMCD to real-world mouse ovarian aging cohorts, we reconstructed a cell-type-specific PCD landscape, bypassing the need for costly single-cell sequencing. Specifically, we identified an age-associated increase in inflammatory and lytic death modalities, together with a strong association between macrophage enrichment and pyroptosis during ovarian aging. Crucially, the DeepMCD-derived PCD fractions exhibit profound divergent correlations with core ovarian fibrosis-related genes. These computationally extracted signatures may serve as cost-effective candidate digital biomarkers for evaluating ovarian fibrosis and reproductive senescence. Ultimately, DeepMCD provides a highly interpretable, robust, and scalable computational tool for bulk RNA-seq data decoding.