HE4 in Cancer and Non-Malignant Disease

HE4 in Cancer and Non-Malignant Disease

Human epididymis protein 4, commonly abbreviated as HE4 and encoded by the WFDC2 (whey acidic protein four-disulfide core domain 2) gene, has traveled a remarkable path from an obscure epididymal transcript to one of the most clinically useful serological biomarkers in gynecologic oncology — and, more unexpectedly, to an emerging signal of tissue fibrosis and cardiovascular stress. Originally identified in the distal epithelium of the human epididymis, HE4 is now appreciated as a secreted glycoprotein whose expression is far broader than its name implies, and whose biological and diagnostic roles continue to expand. This review summarizes the molecular biology of HE4, its established position in ovarian cancer management, its growing footprint across other malignancies, and the surprising recent evidence linking it to heart failure and fibrotic remodeling. Throughout, the aim is to synthesize what makes HE4 distinctive among tumor markers: a favorable specificity profile, a capacity to illuminate disease biology, and an ability to cross the boundary between oncology and non-malignant pathophysiology.

HE4 as an Ovarian Cancer Biomarker

The clinical ascent of HE4 is inseparable from the challenge of ovarian cancer, a disease in which most cases are diagnosed at advanced stages because early symptoms are vague and nonspecific. For decades, cancer antigen 125 (CA125) was the dominant serological marker, yet CA125 suffers from limited specificity: it is frequently elevated in benign gynecological conditions such as endometriosis, adenomyosis, uterine fibroids, and even during menstruation, as well as in a range of non-malignant inflammatory states. HE4's principal advantage is that it is far less often perturbed by these benign mimics, giving it higher specificity and, in several studies, superior performance for detecting early-stage disease. HE4 is expressed predominantly in serous and endometrioid ovarian carcinomas, the histological subtypes that account for the majority of epithelial ovarian cancers, and is only rarely expressed in mucinous or germ cell tumors.

The complementary strengths of HE4 and CA125 have been harnessed in multivariate algorithms that estimate the risk of ovarian malignancy from a pelvic mass. By combining the two markers with menopausal status, such algorithms improve the discrimination between benign and malignant adnexal masses beyond what either marker achieves alone, supporting clinical decision-making about the need for surgical referral to specialist centers. A practical consequence of HE4's biology is that reference intervals differ by menopausal status, with higher upper limits of normal in postmenopausal women, and this stratification is built into the risk algorithms rather than ignored. Beyond diagnosis, serial HE4 measurement has been explored for monitoring treatment response and detecting recurrence earlier than imaging, since rising antigen levels can precede radiological evidence of relapse. The relatively low rate of HE4 elevation in benign disease means that an increasing or persistently elevated HE4 carries meaningful weight in the postoperative surveillance setting. It is worth stressing the specificity advantage quantitatively: whereas CA125 is frequently elevated in endometriosis, pelvic inflammatory disease, liver disease, and menstruation, HE4 remains comparatively quiescent in these contexts, which is precisely why its addition reduces the false-positive referrals that have long plagued ovarian cancer screening.

HE4 in Non-Malignant Disease

Perhaps the most intriguing recent development is the recognition that HE4 is not exclusively an oncological signal. A growing body of cardiovascular research has demonstrated that circulating HE4 is associated with heart failure severity and adverse outcomes. Mechanistically, this appears to reflect HE4's expression by activated myofibroblasts — the cells that drive tissue fibrosis — and its secretion into the extracellular space during fibrotic remodeling. In patients with acute coronary syndrome, baseline HE4 has been shown to predict new-onset heart failure in women over the following year, with a threshold concentration separating high-risk from low-risk individuals. In acute myocardial infarction, elevated HE4 independently predicted major adverse cardiac events during follow-up, and in heart failure with reduced ejection fraction, higher HE4 levels tracked with poorer systolic function and worse event-free survival, even after adjustment for established risk factors including natriuretic peptides and renal function. These findings recast HE4 as a fibrosis-responsive molecule whose elevation in cancer and in cardiac disease may share a common underlying biology: dysregulated extracellular matrix turnover and protease-inhibitory signaling at sites of tissue stress.

The non-malignant relevance of HE4 extends beyond the heart. In renal disease, HE4 has been examined as a marker of fibrotic remodeling and as a correlate of adverse outcomes in patients with end-stage renal disease complicated by acute heart failure, where it tracks with disease severity and prognosis alongside established renal and cardiac biomarkers. Because HE4 is cleared and influenced by renal function, its interpretation in nephrological and cardio-renal contexts requires careful attention to kidney status, and studies appropriately exclude or adjust for advanced renal failure when evaluating cardiac prognosis. The broader implication is that HE4 occupies an unusual position as a protein whose serological elevation can reflect either malignant transformation or stromal fibrotic activation, and disentangling these contributions in individual patients is an active analytical challenge. What is clear is that the marker's biology is richer than its tumor-marker label suggests, and that fibrosis — not cancer alone — may be the unifying process that elevates it.

Figure 2. Vicious cycle of cardiorenal linkage via high HE4.
(Source: Yamamoto M, et al. 2021)

Future of HE4 as a Biomarker

Several directions are likely to define the next phase of HE4 research. First, the mechanistic question of what HE4 actually does in tumor and stromal cells remains only partially answered; clarifying its protease-inhibitory and signaling roles could convert it from a passive marker into a targetable node in oncogenesis and fibrosis, and could explain why high HE4 expression so often tracks with aggressive tumor behavior. Second, the dual oncology-cardiology relevance of HE4 invites integrated studies that examine whether elevated HE4 in cancer patients carries independent prognostic information about cardio-renal comorbidity, an increasingly important consideration as survivorship and cardio-oncology mature as fields and as therapy-related cardiac toxicity becomes a front-line concern. Third, standardization of urine and other non-serum HE4 assays is a prerequisite for the marker's expansion beyond specialist centers, and without reference materials and harmonized cut-offs the marker's full utility will remain locked inside academic cohorts. Finally, the most durable gains are likely to come from combining HE4 with complementary markers and clinical variables in validated algorithms, rather than interpreting it in isolation — a principle that has already proven its worth in ovarian cancer risk estimation and that mirrors the broader shift toward multivariate, AI-assisted diagnostic indexing in laboratory medicine. Whether HE4 ultimately becomes a routine component of multi-cancer early-detection panels or remains anchored in gynecologic and cardiovascular niches, its trajectory illustrates how a single secreted protein can illuminate both the biology of disease and the architecture of modern diagnostics.

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