Daniel José Barbosa ^1,2,3 Joana Barbosa ^1,2 Elaine M. Souza-Fagundes ⁴ Patrícia M. A. Silva ^1,2,5*

• ¹ Associate Laboratory i4HB - Institute for Health and Bioeconomy, University Institute of Health Sciences - CESPU, 4585-116 Gandra, Portugal, Gandra, Portugal
• ² UCIBIO – Applied Molecular Biosciences Unit, Translational Toxicology Research Laboratory, University Institute of Health Sciences (1H-TOXRUN, IUCS-CESPU), 4585-116 Gandra, Portugal, Gandra, Portugal
• ³ Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Porto, Portugal
• ⁴ Departamento de Fisiologia e Biofísica, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil, Minas Gerais, Brazil
• ⁵ UNIPRO – Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS-CESPU), 4585-116 Gandra, Portugal., Gandra, Portugal

Sciences (IUCS-CESPU), 4585-116 Gandra, Portugal. *Correspondence: Patrícia M. A. Silva (patricia.silva@cespu.pt)The balanced regulation of cell death and survival is critical for maintaining the homeostasis of the human body. Disruption of this delicate equilibrium often underlies the development of several diseases. For instance, cancer cells often develop resistance to natural cell death mechanisms, leading to uncontrolled proliferation and malignant growth (1,2). Conversely, neurodegenerative diseases involve the progressive loss of specific brain cell populations, resulting in a broad spectrum of debilitating symptoms and, ultimately, cell death (3, 4) (Figure 1).The incidence and prevalence of both cancer and neurodegenerative diseases are rising rapidly, significantly impacting patients' quality of life and creating major economic and healthcare challenges worldwide (5,6). While knowledge about the role of abnormal cell death in these diseases has advanced, the precise mechanisms driving these processes, as well as effective strategies to modulate them, remain only partially understood. This limited understanding complicates efforts to tailor treatments to different disease types. For instance, in cancer, therapeutic approaches focus on inducing cell death to eliminate malignant cells, whereas in neurodegenerative diseases, the goal shifts to preventing cell death to preserve affected neurons and delay symptom progression. This Research Topic focused on enriching our understanding of the emerging modulators of cell death, exploring their mechanisms of action and potential therapeutic applications in various disease scenarios.In total, two original research articles and three review articles were published. This editorial briefly summarizes the findings and highlights key insights derived from these articles, emphasizing their contributions to the field and the potential they present for guiding future research and/or therapeutic strategies. release in ALL cells is dependent on the Gαi subunit, as its inhibition blocks this process without affecting Gβϒ. Moreover, further experiments showed that activating adenylyl cyclase (AC) with forskolin or using 8-CPT-cAMP inhibits D,L-methadone-induced ER Ca 2+ release, suggesting a Gαi-mediated downregulation of AC and cAMP. Notably, the protein kinase A (PKA) inhibitor 14-22 amide (myr) can independently elicit ER Ca 2+