Multidimensional roles of novel regulated cell death modalities in metabolic dysfunction-associated steatotic liver disease: the interplay network of ferroptosis, cuproptosis, manganese-induced cell death, and pyroptosis

The therapeutic dilemma in metabolic dysfunction-associated steatotic liver disease (MASLD) is rooted in an incomplete understanding of its underlying pathological network. Although novel modalities of regulated cell death (RCD), namely ferroptosis, cuproptosis, manganese-induced cell death and pyroptosis, have been implicated in MASLD progression, current research predominantly treats them as isolated events, largely overlooking their potential intertwining within the liver microenvironment. Herein, we systematically reconfigure the interactive network of these four RCD modalities in MASLD. We further situate this core network within the wider regulated cell death landscape of MASLD by incorporating autophagy and necroptosis as the organelle-level and inflammatory arms that set the threshold for, and amplify, metabolic cell death, and by relating the emerging modalities to classical apoptosis and to PANoptosis (coordinated pyroptosis–apoptosis–necroptosis cell death). We hypothesize that manganese-induced cell death may execute a “systemic antioxidant defense collapse” via selenoprotein deprivation, and that cuproptosis could trigger a “metal homeostasis paralysis” through ATP depletion; together, they might eliminate the endogenous barriers against ferroptosis-driven lipid peroxidation. We further propose that the metabolic debris accumulated by these modalities may subsequently converge on gasdermin D (GSDMD)-mediated pyroptosis, potentially amplifying inflammation and pro-fibrotic cascades. Because concurrent detection of molecular signatures does not establish functional coupling, every interaction proposed in this review is assigned an explicit evidence grade (bioinformatic association, observational, pharmacological, genetic, or direct mechanistic demonstration; Table 1), and all network-level links are labelled as hypotheses. Every mechanism discussed below is additionally assigned to one of three evidential contexts: (i) demonstrated in MASLD models or patients; (ii) demonstrated in other liver diseases or non-hepatic experimental systems, so that its operation in MASLD is an extrapolation; or (iii) proposed on the basis of mechanistic plausibility or computational association and not demonstrated in any experimental system. On this classification the individual inputs to our model—lipid overload, mitochondrial dysfunction, lipid peroxidation, oxidative stress and inflammasome activation—are largely context (i), whereas the copper- and manganese-specific steps that connect them are contexts (ii) and (iii), and the convergence of all of them into a single self-amplifying circuit is context (iii). The conceptualization of this proposed network of interconnected regulatory loops serves as a theoretical framework awaiting experimental validation, marking a transition from linear metabolic stress to multidimensional network failure. Building upon this network reconfiguration, we critically evaluate the limitations of single-target interventions, proposing that future therapeutic strategies should pivot towards multi-node synergistic modulation. Ultimately, integrating spatial multi-omics profiling with a “metal-oxidation-inflammation” biomarker matrix to achieve precise patient stratification will establish a novel translational paradigm for the development of disease-modifying therapies (DMTs) for MASLD.