REV‐ERBα–Mediated Hepatic Regulation of Cachexia: A Circadian‐Metabolic Axis of Tissue Wasting

In the recent article published in Cell [1], Kaltenecker et al. systematically uncovered the liver as an active pathological driver of cancer cachexia (CCx). Through integrated multi-omics analysis, the study identifies the downregulation of the circadian regulator REV-ERBα (nuclear receptor subfamily 1 group D member 1, NR1D1) as a central mechanism that disrupts hepatic homeostasis and induces abnormal secretion of hepatokines, thereby promoting peripheral tissue wasting. These findings provide a conceptual framework for developing therapeutic strategies targeting the “liver–peripheral tissue” axis in CCx. Cancer cachexia is a highly catabolic metabolic syndrome associated with advanced malignancies, characterized by progressive weight loss, skeletal muscle atrophy, and adipose tissue degradation [2, 3]. It is particularly prevalent in pancreatic, gastric, and lung cancers, affecting 50%–80% of patients and accounting for approximately 20% of cancer-related deaths. While previous studies have predominantly focused on local mechanisms of muscle atrophy, such as the ubiquitin-proteasome system (UPS), autophagy, and the NF-κB or FOXO pathways, the systemic metabolic functions of the liver in CCx pathogenesis remain underexplored. Notably, a concurrent study by Garrett et al. published in Cell demonstrated that tumor-driven inflammation can alter the vagal nerve–liver axis, resulting in suppression of hepatic HNF4α and exacerbation of systemic catabolism, further highlighting the critical involvement of the liver in this condition [4]. Given the pivotal role of the liver in systemic metabolism, the authors hypothesized that tissue wasting in cachexia may originate from hepatic responses to tumor-derived signals, which drive peripheral tissue catabolism through the secretion of specific factors. To investigate this, Kaltenecker et al. performed integrated transcriptomic and epigenomic profiling of hepatocytes from both weight-stable and cachectic cancer mouse models. These analyses uncovered a distinct transcriptional program specific to cachexia, characterized by dysregulated expression of the circadian regulator REV-ERBα. Hepatic restoration of REV-ERBα expression markedly attenuated both muscle and fat wasting. Mechanistically, REV-ERBα modulates tissue degradation by controlling hepatokines that activate catabolic pathways in myotubes and adipocytes. Notably, clinical data further revealed elevated circulating levels of key hepatokines in cachectic patients, independent of classical inflammatory cytokines such as IL-6 or TNF-α, underscoring a novel “hepatokine-peripheral tissue” axis in CCx pathophysiology. Delving further into molecular effectors, the authors identified three key liver-secreted proteins-lipopolysaccharide-binding protein (LBP), inter-α-trypsin inhibitor heavy-chain H3 (ITIH3), and insulin-like-growth-factor-binding protein 1 (IGFBP1)–as direct targets of REV-ERBα. Genetic deletion of REV-ERBα/β in mouse hepatocytes markedly increased their hepatic expression. Recombinant LBP, ITIH3, and IGFBP1 induced cardiomyocyte atrophy and stimulated lipolysis in both adipocytes and muscle cells in vitro, whereas in vivo silencing of these hepatic factors substantially mitigated peripheral tissue wasting. Analysis of clinical specimens corroborated these findings, revealing markedly elevated hepatokine levels in cachectic patients that were independent of canonical inflammatory mediators such as IL-6 and TNF-α. These observations suggest that REV-ERBα governs cachexia progression via a previously unrecognized “hepatokine-peripheral tissue” axis (Figure 1A,B). Based on these findings, the authors proposed a comprehensive “liver–REV-ERBα–hepatokine” axis as a key regulatory circuit in CCx: (1) tumor-derived signals disrupt hepatic circadian rhythms via REV-ERBα downregulation, thereby initiating systemic catabolism; (2) aberrant upregulation of hepatokine secretion acts as an executor of body weight loss, adipose lipolysis, and muscle atrophy, among which targeted silencing of IGFBP1 demonstrates notable therapeutic potential; (3) restoring hepatic REV-ERBα expression reverses the abnormal secretory profile, ameliorating cachectic symptoms. This study not only establishes the liver as a causal organ in CCx but also identifies a noncanonical mechanism independent of inflammatory signaling, offering new molecular targets for intervention. Despite the high mechanistic rigor and innovation of the study, several critical questions remain to be addressed. First, the upstream signals responsible for REV-ERBα downregulation remain unclear. The identity of the upstream signal, be it common soluble factors or more discrete tumor-derived molecules such as specific tRNA fragments or epigenetic modifiers targeting the REV-ERBα promoter, is currently unknown. Validating this unique tumor-liver circuit would fundamentally shift therapy from combating downstream catabolism to blocking the tumor's core command, for instance, with targeted blockers designed for this specific pathway. Future studies employing tumor-liver conditional knockout models or coculture systems of tumor and liver organoids may help elucidate these pathways. Second, it is unknown whether REV-ERBα is subject to direct neural regulation. Previous studies suggest that REV-ERBα may also act as a neuroreceptor, potentially responsive to vagal afferent signaling or central circadian outputs-an intriguing hypothesis warranting further investigation in light of Garrett et al.'s proposed “neural-hepatic-peripheral” regulatory axis [5]. Third, While the study delineates the distinct roles of hepatokines in tissue-specific wasting—with LBP and ITIH3 regulating adipose catabolism and IGFBP1 governing muscle atrophy—the precise downstream mechanisms through which they mediate cellular metabolism in target tissues remain entirely unknown. A deeper understanding of these signaling cascades will be critical for the rational design of antagonistic therapies. Fourth, it remains to be determined whether a feedback loop exists whereby metabolic byproducts or immune signals from degenerated tissues influence REV-ERBα expression, potentially forming a closed regulatory circuit-a possibility that merits systematic exploration (Figure 1C). This study provides compelling evidence for the pathophysiological significance of the “liver–REV-ERBα–hepatokine” axis in CCx, with important translational implications. At the diagnostic level, elevated plasma concentrations of LBP, ITIH3, and IGFBP1 could serve as noninvasive biomarkers for early cachexia detection and disease staging. At the therapeutic level, REV-ERBα agonists may restore circadian homeostasis in hepatocytes and suppress hepatokine hypersecretion, while targeted neutralization of LBP, ITIH3, and IGFBP1–via antibodies or small-molecule inhibitors-could directly prevent peripheral tissue loss. Compared with current anti-cachexia strategies that target IL-6 or GDF15, interventions based on this newly identified axis may offer greater organ specificity and improved clinical feasibility. In conclusion, Kaltenecker et al. have constructed an innovative model in which the liver is repositioned from a passive responder to an active driver of cancer cachexia. The “liver–REV-ERBα–hepatokine” axis provides a critical mechanistic bridge between tumor burden and peripheral tissue catabolism, establishing a molecular framework for early intervention and precision therapy. This work paves the way for a transformative shift in CCx research-from symptomatic management to mechanistically targeted interventions. Conceptualization: Junke Song and Gaofei Wei. Writing – original draft: Wenhui Wang. Writing – review and editing: All authors. All authors have read and approved the final manuscript. We thank BioRender.com for the tools available at their platform, which were used to create Figure 1. This work was supported by the National Natural Science Foundation of China (82173682, 22577101, 82374074). The authors have nothing to report. The authors declare no conflicts of interest. The authors have nothing to report.